ADHD and norepinephrine / epinephrine


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(Updated 1/25/04)

Biederman J, Spencer T.
Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder.
Biol Psychiatry 1999 Nov 1;46(9):1234-42
"This review revisits the thesis that a dysregulation of the central noradrenergic networks may underlie the pathophysiology of ADHD. We review the pertinent neurobiological and pharmacological literature on ADHD. The noradrenergic system has been intimately associated with the modulation of higher cortical functions including attention, alertness, vigilance and executive function. Noradrenergic activation is known to profoundly affect the performance of attention, especially the maintenance of arousal, a cognitive function known to be deficient in ADHD. Data from family, adoption, twin, and segregation analysis strongly support a genetic hypothesis for this disorder. Although molecular genetic studies of ADHD are relatively new and far from definitive, several replicated reports have found associations between ADHD with DAT and D4 receptor genes. Brain imaging studies fit well with the idea that dysfunction in fronto-subcortical pathways occurs in ADHD with its underlying dysregulation of noradrenergic function. A wealth of pharmacological data (within and without the stimulant literature) provides strong evidence for selective clinical activity in ADHD for drugs with noradrenergic and dopaminergic pharmacological profiles. Available research provides compelling theoretic, basic biologic and clinical support for the notion that ADHD is a brain disorder of likely genetic etiology with etiologic and pathophysiologic heterogeneity. Neurobiological and pharmacological data provide compelling support for a noradrenergic hypothesis of ADHD and suggest that drugs with noradrenergic activity may play an important role in the therapeutics of this disorder." [Abstract]

Halperin JM, Newcorn JH, Koda VH, Pick L, McKay KE, Knott P.
Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension.
J Am Acad Child Adolesc Psychiatry 1997 Dec;36(12):1688-97
"OBJECTIVE: To examine noradrenergic (NA) function in children with attention-deficit hyperactivity disorder (ADHD) by replicating and expanding upon a previous finding that ADHD children with and without reading disabilities (RD) differ in plasma levels of the NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). METHOD: Plasma levels of MHPG were compared in ADHD children who were subdivided on the basis of the presence or absence of RD. Subsequently, this replication sample was combined with a previously studied sample to further explore the relationship between plasma MHPG levels and measures of cognitive function in children with ADHD. RESULTS: Plasma levels of MHPG were significantly lower in ADHD children without RD, compared with those with RD, replicating a published finding. Analyses in the combined sample indicated that, among children with ADHD, plasma MHPG levels were inversely associated with measures of academic achievement and verbal processing, but not parent or teacher ratings of behavior or continuous performance test measures of attention and impulsivity. CONCLUSIONS: These data indicate that children with ADHD are not homogeneous with regard to NA function and that neurochemical variation is closely associated with differences in clinical characteristics of the children." [Abstract]

Shekim WO, Sinclair E, Glaser R, Horwitz E, Javaid J, Bylund DB.
Norepinephrine and dopamine metabolites and educational variables in boys with attention deficit disorder and hyperactivity.
J Child Neurol 1987 Jan;2(1):50-6
"The present study evaluated the biochemical measures of urinary homovanillic acid (HVA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) in relation to functioning on selected psychoeducational tests in a group of boys with attention deficit disorder and hyperactivity. The Wechsler Intelligence Scale for Children-Revised (WISC-R), the Wide Range Achievement Test (WRAT), and the Peabody Picture Vocabulary Test were administered to 28 hyperactive and 23 control subjects. The findings suggest subtle differences in psychoeducational test performance in relation to specific levels of homovanillic acid and MHPG." [Abstract]

Pliszka SR, Maas JW, Javors MA, Rogeness GA, Baker J.
Urinary catecholamines in attention-deficit hyperactivity disorder with and without comorbid anxiety.
J Am Acad Child Adolesc Psychiatry 1994 Oct;33(8):1165-73
"OBJECTIVE: To determine whether there are differences in noradrenergic or adrenergic functioning in children with attention-deficit hyperactivity disorder (ADHD) with and without anxiety. METHOD: ADHD children with and without a comorbid overanxious (ANX) disorder were compared to each other and to normal controls in terms of 2-hour urinary excretion of norepinephrine (NE), epinephrine (EPI), and their metabolites. All subjects performed a fixed series of mentally stressful tasks during the collection period. RESULTS: Children with ADHD, regardless of comorbid anxiety, excreted more normetanephrine (NMN), the chief extracellular metabolite of NE, than controls, as well as more vanillylmandelic acid. Children with ADHD alone had lower NE/NMN and EPI/metanephrine ratios compared to controls. Children with ADHD/ANX excreted more EPI than ADHD children without anxiety. CONCLUSIONS: Children with ADHD may have a higher tonic activity of the noradrenergic system than controls, while children with comorbid ADHD/ANX may be differentiated from those with ADHD alone by higher adrenergic activity." [Abstract]

Hanna GL, Ornitz EM, Hariharan M.
Urinary catecholamine excretion and behavioral differences in ADHD and normal boys.
J Child Adolesc Psychopharmacol 1996 Spring;6(1):63-73
"Urinary catecholamine excretion was assessed in 15 boys with attention-deficit/hyperactivity disorder (ADHD) and 16 normal controls during a defined physical and mental task. Dihydroxyphenylalanine, dopamine, norepinephrine (NE), epinephrine (EPI), 3,4-dihydroxyphenylacetic acid, and 3,4-dihydroxyphenylglycol (DOPEG) concentrations were assayed by high-pressure liquid chromatography with electrochemical detection. The urinary concentration of DOPEG, an NE metabolite that has not been previously measured in ADHD, was significantly lower in the ADHD subjects than in the normal controls. There was also a trend for lower urinary EPI levels in the hyperactive boys. Stepwise multiple regression analyses demonstrated that DOPEG and EPI each contributed significantly to the variance in the behavioral symptoms within the full sample. The results are consistent with previous reports of abnormal metabolism of norepinephrine and epinephrine in ADHD. These neurochemical findings may be due to differences between ADHD and normal boys in neuronal (central or peripheral) or nonneuronal (e.g., adrenal, renal) activity. The results are also consistent with prior findings in normal children of an inverse relationship between EPI excretion and inattentive, restless behaviors. Together, these findings suggest caution in ascribing metabolite changes to ADHD or to ADHD-like behaviors that may be seen in normal children." [Abstract]

Wigal SB, Nemet D, Swanson JM, Regino R, Trampush J, Ziegler MG, Cooper DM.
Catecholamine Response to Exercise in Children with Attention Deficit Hyperactivity Disorder.
Pediatr Res 2003 Mar 5; [epub ahead of print]
"The objective of this study was to examine differences in catecholamine (CA) response to exercise between children who had received a diagnosis of attention-deficit/hyperactivity disorder (ADHD) and age- and sex-matched controls. On the basis of the notion of a CA dysfunction in ADHD, we reasoned that the normal robust increase in circulating CA seen in response to exercise would be blunted in children with ADHD. To test this, we recruited 10 treatment-naive children with newly diagnosed ADHD and 8 age-matched controls (all male) and measured CA response to an exercise test in which the work was scaled to each subject's physical capability. After exercise, epinephrine and norepinephrine increased in both control and ADHD subjects (p = 0.006 and p = 0.002, respectively), but the responses were substantially blunted in the ADHD group (p = 0.018) even though the work performed did not differ from controls. Circulating dopamine increased significantly in the control subjects (p < 0.016), but no increase was noted in the subjects with ADHD. Finally, a significant attenuation in the lactate response to exercise was found in ADHD (between groups, p < 0.005). Our data suggest that CA excretion after exercise challenges in children with ADHD is deficient. This deficiency can be detected using a minimally invasive, nonpharmacologic challenge." [Abstract]

Anderson GM, Dover MA, Yang BP, Holahan JM, Shaywitz SE, Marchione KE, Hall LM, Fletcher JM, Shaywitz BA.
Adrenomedullary function during cognitive testing in attention-deficit/hyperactivity disorder.
J Am Acad Child Adolesc Psychiatry 2000 May;39(5):635-43
"OBJECTIVE: Reported correlations between epinephrine (EPI) excretion and classroom performance, the cognition-enhancing effects of EPI infusion, increased EPI excretion with stimulants, and reports of decreased EPI excretion in attention-deficit/hyperactivity disorder (ADHD) suggest that sympathoadrenomedullary function might be altered in ADHD. This hypothesis was tested by examining sympathetic and adrenomedullary functioning during cognitive testing in boys with diagnosed ADHD. METHOD: Urinary excretion of EPI and norepinephrine during a 3-hour cognitive test battery was assessed in 7- to 13-year-old boys. Excretion rates (nanograms per hour per square meter of body surface area) were determined in 200 individuals with ADHD (diagnosed according to DSM-IV criteria), with or without co-occurring oppositional defiant/conduct disorder or learning disorder. A non-ADHD contrast group (n = 51) with similar comorbidity was also studied. RESULTS: Substantially lower (mean +/- SE) urinary EPI excretion was observed in the ADHD-inattentive subtype (n = 71) compared with the control group (200 +/- 22 versus 278 +/- 24 ng/hr/m2; F = 5.99, p = .015, critical alpha = .017). No diagnostic group differences were seen for norepinephrine excretion. Correlational analysis of both parent- and teacher-rated behaviors revealed that inattention factors consistently negatively predicted urinary EPI excretion. CONCLUSIONS: The data extend findings of lower adrenomedullary activity during cognitive challenge in individuals with ADHD and suggest that the alteration is associated with inattentive behavior." [Abstract]

Girardi NL, Shaywitz SE, Shaywitz BA, Marchione K, Fleischman SJ, Jones TW, Tamborlane WV.
Blunted catecholamine responses after glucose ingestion in children with attention deficit disorder.
Pediatr Res 1995 Oct;38(4):539-42
"Eating simple sugars has been suggested as having adverse behavioral and cognitive effects in children with attention deficit disorder (ADD), but a physiologic mechanism has not been established. To address this issue, metabolic, hormonal, and cognitive responses to a standard oral glucose load (1.75 g/kg) were compared in 17 children with ADD and 11 control children. Baseline and oral glucose-stimulated plasma glucose and insulin levels were similar in both groups, including the nadir glucose level 3-5 h after oral glucose (3.5 +/- 0.2 mmol/L in ADD and 3.3 +/- 0.2 mmol/L in control children). The late glucose fall stimulated a rise in plasma epinephrine that was nearly 50% lower in ADD than in control children (1212 +/- 202 pmol/L versus 2228 +/- 436 pmol/L, p < 0.02). Plasma norepinephrine levels were also lower in ADD than in control children, whereas growth hormone and glucagon concentrations did not differ between the groups. Matching test scores were lower and reaction times faster in ADD than in control children before and after oral glucose, and both groups showed a deterioration on the continuous performance test in association with the late fall in glucose and rise in epinephrine. These data suggest that children with ADD have a general impairment of sympathetic activation involving adrenomedullary as well as well as central catecholamine regulation." [Abstract]

Matsuishi T, Yamashita Y.
[Neurochemical and neurotransmitter studies in patients with learning disabilities]
No To Hattatsu 1999 May;31(3):245-8
"To clarify the pathophysiology of learning disability (LD), we measured the urinary levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), and phenylethylamine (PEA) in urine samples collected in a 24 hour period. Findings were compared with those obtained in age-matched controls and diseased controls including patients with attention deficit-hyperactivity disorder (ADHD), infantile autism, and mental retardation. The mean urinary level of MHPG in LD (n = 6) were not significantly different from those in ADHD (n = 16), mental retardation (n = 4), infantile autism (n = 5), and the controls (n = 6), while the mean urinary levels of PEA were significantly lower in LD (n = 6, 91 +/- 17.3 micrograms/mg) and in ADHD (n = 5, 65 +/- 53.6 micrograms/mg) as compared to age-matched controls (n = 3, 340 +/- 264.5 micrograms/mg) ANOVA, (p < 0.05). PEA is considered to play an important role for the pathogenesis of LD and ADHD." [Abstract]

Baker GB, Bornstein RA, Douglass AB, Van Muyden JC, Ashton S, Bazylewich TL.
Urinary excretion of MHPG and normetanephrine in attention deficit hyperactivity disorder.
Mol Chem Neuropathol 1993 Jan-Feb;18(1-2):173-8
"Twenty-four-hour excretion (expressed per gram of creatinine) of the norepinephrine metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NME) was measured in children with attention deficit hyperactivity disorder (ADHD) and in normal subjects matched for age and education. In contrast to findings with Tourette syndrome patients, in the ADHD patients there was no significant difference in excretion of MHPG and NME from control values."

Spencer TJ, Biederman J, Wilens TE, Faraone SV.
Novel treatments for attention-deficit/hyperactivity disorder in children.
J Clin Psychiatry 2002;63 Suppl 12:16-22
"Optimal medications for children with attention-deficit/hyperactivity disorder (ADHD) would be effective, well tolerated, and long acting and not cause mood swings or worsen comorbid conditions. Current medications work on brain dopamine and/or norepinephrine systems, which are thought to be involved in ADHD. The medication class with the most evidence of efficacy in ADHD is stimulants, but they may be abused, are effective for only 4 to 12 hours, and may cause mood swings or increase tic severity. In recent years, alternative treatments have been explored. Tricyclic antidepressants have efficacy comparable to that of stimulants but may cause constipation, dry mouth, tremors, blood pressure changes, and potentially serious side effects including cardiac conduction and repolarization delays. Monoamine oxidase inhibitors may improve ADHD symptoms but are associated with severe dietary restrictions. Serotonin reuptake inhibitors have little or no effect in ADHD but may improve comorbid depression. Bupropion, although less effective than stimulants, may improve both ADHD symptoms and comorbid depression. Antihypertensive agents may improve impulsivity, hyperactivity, and comorbid tics but cause sedation or rebound hypertension. Atomoxetine, which is being developed for ADHD, reduces symptoms of ADHD without exacerbating comorbid conditions and is associated with only minor side effects, including subtle changes in blood pressure and heart rate. Before prescribing a treatment, physicians should consider the appropriateness and effectiveness of any medication for children with ADHD, who may be less tolerant of side effects and less able to monitor and express concerns about their well-being than adults." [Abstract]

Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.
Neuropsychopharmacology 2002 Nov;27(5):699-711
"The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX) levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX). We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities." [Abstract]

Stahl SM.
Neurotransmission of cognition, part 3. Mechanism of action of selective NRIs: both dopamine and norepinephrine increase in prefrontal cortex.
J Clin Psychiatry. 2003 Mar; 64(3): 230-1.
"ISSUE: Selective norepinephrine reuptake inhibitors exploit the fact that dopamine transporters are absent in prefrontal cortex, so dopamine has to hitchhike a ride on the norepinephrine transporter in order to be inactivated. Thus, blocking norepinephrine transporters leads to an increase in both dopamine and norepinephrine levels in prefrontal cortex as well as improvement in cognition in attention-deficit/hyperactivity disorder." [Abstract]

Wernicke JF, Kratochvil CJ.
Safety profile of atomoxetine in the treatment of children and adolescents with ADHD.
J Clin Psychiatry 2002;63 Suppl 12:50-5
"Atomoxetine is a selective norepinephrine reuptake inhibitor that is being developed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine will be the first nonstimulant medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD. Throughout the testing phases, more than 2000 children and adolescents have been exposed to atomoxetine in clinical trials, with both the number of exposures and the length of exposure time increasing. Serious adverse events have not been clearly associated with the drug, and there have been few discontinuations due to adverse events. The most common drug-related event reported in trials has been decreased appetite and an initial period of weight loss followed by an apparently normal rate of weight gain. These events tend to appear early in the course of treatment with atomoxetine and then decline. Atomoxetine has also been associated with mild increases in blood pressure and pulse that plateau during treatment and resolve upon discontinuation. There have been no effects seen on the QT interval, and the cytochrome P450 2D6 metabolism of patients seems to have little effect on safety or tolerability of the drug. This article will review the data from completed and ongoing clinical trials available at the time the New Drug Application was submitted to the FDA. Described are serious adverse events, discontinuations, and treatment-emergent adverse events. Specifically, cardiac effects and effects on weight, height, and metabolism that are related to treatment of ADHD with atomoxetine in children and adolescents are discussed." [Abstract]

Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich A, Milton D.
Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies.
Biol Psychiatry 2003 Jan 15;53(2):112-20
"Attention-deficit/hyperactivity disorder (ADHD) has been less studied in adults than in children, and the treatment studies reported to date have been small, single-center trials. To assess the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, we conducted two large, multicenter treatment trials.Two identical studies using randomized, double-blind, placebo-controlled designs and a 10-week treatment period were conducted in adults with DSM-IV-defined ADHD as assessed by clinical history and confirmed by a structured interview (study I, n = 280; study II, n = 256). The primary outcome measure was a comparison of atomoxetine and placebo using repeated measures mixed model analysis of postbaseline values of the Conners' Adult ADHD Rating Scale.In each study, atomoxetine was statistically superior to placebo in reducing both inattentive and hyperactive and impulsive symptoms as assessed by primary and secondary measures. Discontinuations for adverse events among atomoxetine patients were under 10% in both studies.Atomoxetine appears to be an efficacious treatment for adult ADHD. Its lack of abuse potential may be an advantage for many patients." [Abstract]

Spencer T, Heiligenstein JH, Biederman J, Faries DE, Kratochvil CJ, Conners CK, Potter WZ.
Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder.
J Clin Psychiatry 2002 Dec;63(12):1140-7
"BACKGROUND: Atomoxetine is a nonstimulant drug being studied for the treatment of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine is a highly specific inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. Results of 2 proof-of-concept studies are reported that tested the hypothesis that a selective inhibitor of presynaptic norepinephrine uptake would be effective for the treatment of ADHD in school-aged children. METHOD: Two identical 12-week, stratified, randomized, double-blind, placebo-controlled trials were conducted in children who met DSM-IV criteria for ADHD. The primary efficacy outcome measure was the mean change from baseline to endpoint in the Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD RS) total score. Secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S). RESULTS: A total of 291 patients were randomized in the 2 trials combined (Study 1, N = 147; Study 2, N = 144). Stimulant-naive patients were randomized to atomoxetine, placebo, or methylphenidate. Patients with prior stimulant exposure were randomized to atomoxetine or placebo. Atomoxetine significantly reduced ADHD RS total scores compared with placebo in each study (p <.001). Changes in the CGI-ADHD-S (Study 1: p =.003; Study 2: p =.001) and CPRS-ADHD Index (Study 1: p =.023; Study 2: p <.001) also showed atomoxetine to be statistically significantly superior to placebo in reducing ADHD symptoms. Atomoxetine was found to be well tolerated in this population of pediatric patients. CONCLUSION: Two studies of atomoxetine early in its development confirmed that atomoxetine, a specific and selective inhibitor of noradrenergic uptake, was effective for the treatment of children with ADHD. In addition, atomoxetine was found to be well tolerated." [Abstract]

Biederman J, Heiligenstein JH, Faries DE, Galil N, Dittmann R, Emslie GJ, Kratochvil CJ, Laws HF, Schuh KJ; Atomoxetine ADHD Study Group.
Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder.
Pediatrics 2002 Dec;110(6):e75
"OBJECTIVE: The efficacy of atomoxetine was assessed in school-age girls with attention-deficit/hyperactivity disorder (ADHD). Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors. METHODS: A total of 291 children who were 7 to 13 years of age and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD participated in 1 of 2 combined, double-blind, placebo-controlled, multisite, identical clinical trials. This intent-to-treat subset analysis examined the effects of atomoxetine versus placebo in 51 girls who were randomized to atomoxetine (n = 30) or placebo (n = 21) for 9 weeks. ADHD symptoms were assessed using parent- and investigator-rated scales. RESULTS: Atomoxetine was superior to placebo on the following measures: the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score; the Inattentive and Hyperactive/Impulsive subscales of the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score; the ADHD Index subscale of the Conners' Parent Rating Scale-Revised: Short Form; and the Clinical Global Impressions of Severity of ADHD. Statistically significant efficacy was seen 1 week after randomization and remained so for the duration of the study. One patient from each of the atomoxetine and placebo groups discontinued the study as a result of an adverse event. CONCLUSION: Atomoxetine was found to be effective and well tolerated for the treatment of ADHD in school-age girls." [Abstract]

Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, Spencer T; Atomoxetine ADHD Study Group.
Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study.
Pediatrics 2001 Nov;108(5):E83
"OBJECTIVE: Atomoxetine is an investigational, nonstimulant pharmacotherapy being studied as potential treatment for attention-deficit/hyperactivity disorder (ADHD). It is thought to act via blockade of the presynaptic norepinephrine transporter in the brain. We assessed the efficacy of 3 doses of atomoxetine compared with placebo in children and adolescents with ADHD. METHODS: A total of 297 children and adolescents who were 8 to 18 years of age and had ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, were randomized to placebo or atomoxetine dosed on a weight-adjusted basis at 0.5 mg/kg/day, 1.2 mg/kg/day, or 1.8 mg/kg/day for an 8-week period. ADHD symptoms, affective symptoms, and social and family functioning were assessed using parent and investigator rating scales. RESULTS: Approximately 71% of children enrolled were male, approximately 67% met criteria for mixed subtype (both inattentive and hyperactive/impulsive symptoms), and the only common psychiatric comorbidity was oppositional defiant disorder (approximately 38% of the sample). At baseline, symptom severity was rated as moderate to severe for most children. At endpoint, atomoxetine 1.2 mg/kg/day and 1.8 mg/kg/day were consistently associated with superior outcomes in ADHD symptoms compared with placebo and were not different from each other. The dose of 0.5 mg/kg/day was associated with intermediate efficacy between placebo and the 2 higher doses, suggesting a graded dose-response. Social and family functioning also were improved in the atomoxetine groups compared with placebo with statistically significant improvements in measures of children's ability to meet psychosocial role expectations and parental impact. Discontinuations as a result of adverse events were <5% for all groups. CONCLUSION: Among children and adolescents aged 8 to 18, atomoxetine was superior to placebo in reducing ADHD symptoms and in improving social and family functioning symptoms. Atomoxetine was associated with a graded dose-response, and 1.2 mg/kg/day seems to be as effective as 1.8 mg/kg/day and is likely to be the appropriate initial target dose for most patients. Treatment with atomoxetine was safe and well tolerated." [Abstract]

Kratochvil CJ, Heiligenstein JH, Dittmann R, Spencer TJ, Biederman J, Wernicke J, Newcorn JH, Casat C, Milton D, Michelson D.
Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial.
J Am Acad Child Adolesc Psychiatry 2002 Jul;41(7):776-84
"OBJECTIVE: To assess the comparability of atomoxetine, a new therapy for attention-deficit/hyperactivity disorder (ADHD) and methylphenidate. (Atomoxetine was originally called tomoxetine. The name was recently changed in order to avoid any potential confusion with tamoxifen that might lead to errors in dispensing drug.) METHOD: Children with ADHD were randomized to open-label atomoxetine or methylphenidate for 10 weeks. Response was assessed with the ADHD-IV Rating Scale. RESULTS: Two hundred twenty-eight patients were randomized (atomoxetine n = 184, methylphenidate n = 44). Both drugs were associated with marked improvement in inattentive and hyperactive-impulsive symptom clusters as assessed by parents and investigators. No statistically significant differences between treatment groups were observed on the primary outcome measure (investigator-rated ADHD-IV Rating Scale total score: atomoxetine baseline: 39.4 [8.5], endpoint: 20.0 [13.9]; methylphenidate baseline: 37.6 [9.7], endpoint: 19.8 (16.6); p = .66). Safety and tolerability were also similar between the 2 drugs. Discontinuations due to adverse events were 10/184 (5.4%) for atomoxetine and 5/44 (11.4%) for methylphenidate; p = .175. CONCLUSION: These data provide preliminary evidence that atomoxetine is associated with therapeutic effects comparable to those of methylphenidate." [Abstract]

Michelson D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C, Newcorn J, Sallee FR, Sangal RB, Saylor K, West S, Kelsey D, Wernicke J, Trapp NJ, Harder D.
Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study.
Am J Psychiatry 2002 Nov;159(11):1896-901
"OBJECTIVE: The authors assessed the efficacy of once-daily atomoxetine administration in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: In a double-blind study, children and adolescents with ADHD (N=171, age range=6-16 years) were randomly assigned to receive 6 weeks of treatment with either atomoxetine (administered once daily) or placebo. RESULTS: Outcomes among atomoxetine-treated patients were superior to those of the placebo treatment group as assessed by investigator, parent, and teacher ratings. The treatment effect size (0.71) was similar to those observed in previous atomoxetine studies that used twice-daily dosing. Parent diary ratings suggested that drug-specific effects were sustained late in the day. Discontinuations due to adverse events were low (less than 3%) for both treatment groups, and no serious safety concerns were observed. CONCLUSIONS: Once-daily administration of atomoxetine is an effective treatment for children and adolescents with ADHD." [Abstract]

Overtoom CC, Verbaten MN, Kemner C, Kenemans JL, van Engeland H, Buitelaar JK, van der Molen MW, van der Gugten J, Westenberg H, Maes RA, Koelega HS.
Effects of methylphenidate, desipramine, and L-dopa on attention and inhibition in children with Attention Deficit Hyperactivity Disorder.
Behav Brain Res. 2003 Oct 17; 145(1-2): 7-15.
"The objective of this study was to investigate the effects of methylphenidate (MPH) on attention and inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD) and to establish what the relative contributions of the noradrenergic and dopaminergic systems to this effect were. In addition to MPH, two other drugs were administered in order to affect both transmitter systems more selectively, L-dopa (dopamine (DA) agonist) and desipramine (DMI) (noradrenaline (NA) re-uptake inhibitor). Sixteen children with ADHD performed a stop-task, a laboratory task that measures the ability to inhibit an ongoing action, in a double-blind randomized within-subjects design. Each child received an acute clinical dose of MPH, DMI, L-dopa, and placebo; measures of performance and plasma were determined. The results indicated that inhibition performance was improved under DMI but not under MPH or L-dopa. The response-time to the stop-signal was marginally shortened after intake of DMI. MPH decreased omission and choice-errors and caused faster reaction times to the trials without the stop-tone. No effects of L-dopa whatsoever were noted. Prolactin levels were increased and 5-HIAA levels were lowered under DMI relative to placebo. It is suggested that the effects of MPH on attention are due to a combination of noradrenergic and dopaminergic mechanisms. The improved inhibition under DMI could be serotonergically mediated." [Abstract]

Aston-Jones G, Rajkowski J, Cohen J.
Role of locus coeruleus in attention and behavioral flexibility.
Biol Psychiatry 1999 Nov 1;46(9):1309-20
"Previous findings have implicated the noradrenergic locus coeruleus (LC) system in functions along the dimension of arousal or attention. It has remained uncertain what role this system has in attention, or what mechanisms may be involved. We review our recent work examining activity of LC neurons in monkeys performing a visual discrimination task that requires focused attention. Results indicate that LC cells exhibit phasic or tonic modes of activity, that closely correspond to good or poor performance on this task, respectively. A computational model was used to simulate these results. This model predicts that alterations in electrotonic coupling among LC cells may produce the different modes of activity and corresponding differences in performance. This model also indicates that the phasic mode of LC activity may promote focused or selective attention, whereas the tonic mode may produce a state of high behavioral flexibility or scanning attentiveness. The implications of these results for clinical disorders such as attention-deficit hyperactivity disorder, stress disorders, and emotional and affective disorders are discussed." [Abstract]

Berridge CW, Waterhouse BD.
The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes.
Brain Res Brain Res Rev. 2003 Apr;42(1):33-84.
"Through a widespread efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. Initial studies provided critical insight into the basic organization and properties of this system. More recent work identifies a complicated array of behavioral and electrophysiological actions that have in common the facilitation of processing of relevant, or salient, information. This involves two basic levels of action. First, the system contributes to the initiation and maintenance of behavioral and forebrain neuronal activity states appropriate for the collection of sensory information (e.g. waking). Second, within the waking state, this system modulates the collection and processing of salient sensory information through a diversity of concentration-dependent actions within cortical and subcortical sensory, attention, and memory circuits. Norepinephrine-dependent modulation of long-term alterations in synaptic strength, gene transcription and other processes suggest a potentially critical role of this neurotransmitter system in experience-dependent alterations in neural function and behavior. The ability of a given stimulus to increase locus coeruleus discharge activity appears independent of affective valence (appetitive vs. aversive). Combined, these observations suggest that the locus coeruleus-noradrenergic system is a critical component of the neural architecture supporting interaction with, and navigation through, a complex world. These observations further suggest that dysregulation of locus coeruleus-noradrenergic neurotransmission may contribute to cognitive and/or arousal dysfunction associated with a variety of psychiatric disorders, including attention-deficit hyperactivity disorder, sleep and arousal disorders, as well as certain affective disorders, including post-traumatic stress disorder. Independent of an etiological role in these disorders, the locus coeruleus-noradrenergic system represents an appropriate target for pharmacological treatment of specific attention, memory and/or arousal dysfunction associated with a variety of behavioral/cognitive disorders." [Abstract]

Tan CM, Wilson MH, MacMillan LB, Kobilka BK, Limbird LE.
Heterozygous alpha 2A-adrenergic receptor mice unveil unique therapeutic benefits of partial agonists.
Proc Natl Acad Sci U S A 2002 Sep 17;99(19):12471-6
"Genetic manipulation of the alpha(2A)-adrenergic receptor (alpha(2A)-AR) in mice has revealed the role of this subtype in numerous responses, including agonist-induced hypotension and sedation. Unexpectedly, alpha(2)-agonist treatment of mice heterozygous for the alpha(2A)-AR (alpha(2A)-AR(+/-)) lowers blood pressure without sedation, indicating that more than 50% of alpha(2A)-AR must be activated to evoke sedation. We postulated that partial activation of alpha(2A)-AR in wild-type alpha(2A)-AR(+/+) animals could be achieved with partial agonists, agents with variable ability to couple receptor occupancy to effector activation, and might elicit one versus another pharmacological response. In vitro assays reveal that moxonidine is a partial agonist at alpha(2A)-AR. Although moxonidine was developed to preferentially interact with imidazoline binding sites, it requires the alpha(2A)-AR to lower blood pressure because we observe no hypotensive response to moxonidine in alpha(2A)-AR-null (alpha(2A)-AR(-/-)) mice. Moreover, we observe that moxonidine lowers blood pressure without sedation in wild-type mice, consistent with the above hypothesis regarding partial agonists. Our findings suggest that weak partial agonists can evoke response-selective pathways and might be exploited successfully to achieve alpha(2A)-AR pharmacotherapy where concomitant sedation is undesirable, i.e., in treatment of depression or attention deficit hyperactivity disorder, in suppression of epileptogenesis, or enhancement of cognition. Furthermore, rigorous physiological and behavioral assessment of mice heterozygous for particular receptors provides a general strategy for elucidation of pathways that might be selectively activated by partial agonists, thus achieving response-specific therapy." [Abstract]

Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF.
Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine.
J Neurosci 2002 Oct 1;22(19):8771-7
"Norepinephrine strengthens the working memory, behavioral inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic alpha2-adrenoceptors (alpha2-AR). The alpha2-AR agonist guanfacine enhances prefrontal cortical functions in rats, monkeys, and human beings and ameliorates prefrontal cortical deficits in patients with attention deficit hyperactivity disorder. The present study examined the subtype of alpha2-AR underlying these beneficial effects. Because there are no selective alpha2A-AR, alpha2B-AR, or alpha2C-AR agonists or antagonists, genetically altered mice were used to identify the molecular target of the action of guanfacine. Mice with a point mutation of the alpha2A-AR, which serves as a functional knock-out, were compared with wild-type animals and with previously published studies of alpha2C-AR knock-out mice (Tanila et al., 1999). Mice were adapted to handling on a T maze and trained on either a spatial delayed alternation task that is sensitive to prefrontal cortical damage or a spatial discrimination control task with similar motor and motivational demands but no dependence on prefrontal cortex. The effects of guanfacine on performance of the delayed alternation task were assessed in additional groups of wild-type versus alpha2A-AR mutant mice. We observed that functional loss of the alpha2A-AR subtype, unlike knock-out of the alpha2C-AR subtype, weakened performance of the prefrontal cortical task without affecting learning and resulted in loss of the beneficial response to guanfacine. These data demonstrate the importance of alpha2A-AR subtype stimulation for the cognitive functions of the prefrontal cortex and identify the molecular substrate for guanfacine and novel therapeutic interventions." [Abstract]

Taylor FB, Russo J.
Comparing guanfacine and dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder.
J Clin Psychopharmacol 2001 Apr;21(2):223-8
"The objective of this study was to compare the efficacy of the alpha-2a agonist guanfacine with that of dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder (ADHD). Seventeen adult outpatients who met DSM-IV criteria for ADHD participated in a double-blind, placebo-controlled, crossover study comparing drug effects on ADHD symptoms. Measures of change included the DSM-IV ADHD Behavior Checklist for Adults and the Copeland Symptom Checklist for Adult Attention Deficit Disorders. Cognitive measures of attention included the Stroop and Controlled Oral Word Association Test using the letters "C," "F," and "L" (COWAT, CFL version). For each trial, the drug was administered daily and titered up to optimal doses of maximum efficacy but with a minimum of side effects, and then data were collected. Both drugs significantly reduced ADHD symptoms on the DSM-IV Adult Behavior Checklist for Adults over placebo (p < 0.05). The Stroop Color subscale showed significant improvement for both drugs (p < 0.05), but the Color-Word measures showed significant improvement for guanfacine only (p < 0.01). The average dose of guanfacine was 1.10 (SD = 0.60), and the most common side effect of guanfacine was fatigue. No subjects discontinued drug trials. This preliminary study indicates that guanfacine may be a well-tolerated treatment option for adult ADHD." [Abstract]

Shekim WO, Bylund DB, Hodges K, Glaser R, Ray-Prenger C, Oetting G.
Platelet alpha 2-adrenergic receptor binding and the effects of d-amphetamine in boys with attention deficit hyperactivity disorder.
Neuropsychobiology 1994;29(3):120-4
"Presynaptic inhibitory alpha-adrenergic receptors are involved in regulating the release of norepinephrine (NE) through a negative feedback mechanism mediated by NE. Increased alpha2-adrenergic receptor activity suggests decrease NE release and activity, while decreased alpha2-adrenergic activity suggests increase NE release and activity. A large body of evidence suggests the involvement of a disturbance in NE activity in the pathophysiology of attention deficit hyperactivity disorder (ADHD) in childhood. Platelet alpha2-adrenergic receptor binding was compared in 23 boys aged 7-12 with the diagnosis of ADHD and 11 normal controls. The ADHD boys tended to have lower levels of alpha2-binding than controls. The administration of d-amphetamine in a double-blind placebo-controlled crossover design did not have any effect on alpha2-receptor binding in ADHD boys. Nonresponders to d-amphetamine had the lowest alpha2-receptor binding compared to responders and controls. These findings suggest a normal alpha2-adrenergic activity in ADHD boys responders to d-amphetamine and a possible increase in NE release in ADHD boys nonresponders to d-amphetamine due to decreased alpha2-adrenergic receptors." [Abstract]

Elia J, Borcherding BG, Potter WZ, Mefford IN, Rapoport JL, Keysor CS.
Stimulant drug treatment of hyperactivity: biochemical correlates.
Clin Pharmacol Ther 1990 Jul;48(1):57-66
"To compare the effects of the stimulant drugs dextroamphetamine and methylphenidate on urinary and plasma monoamines and metabolites within the same clinical sample, thirty-one children with attention-deficit disorder with hyperactivity were treated with dextroamphetamine (up to 1.5 mg/kg/day), methylphenidate (up to 3.0 mg/kg/day), and placebo in an 11-week double-blind crossover trial. As expected, both drugs showed striking clinical efficacy, and within a subsample of the group, earlier findings were confirmed, that dextroamphetamine but not methylphenidate lowered urinary and plasma 3-methoxy-4-hydroxyphenylglycol and whole body norepinephrine turnover, and that urinary and plasma concentration of homovanillic acid was unaltered by either drug. Methylphenidate but not dextroamphetamine increased plasma norepinephrine. Urinary epinephrine and metanephrine were increased with both drugs, but this increase did not correlate significantly with clinical improvement." [Abstract]

Shekim WO, Javaid J, Dekirmenjian H, Chapel JL, Davis JM.
Effects of d-amphetamine on urinary metabolites of dopamine and norepinephrine in hyperactive boys.
Am J Psychiatry 1982 Apr;139(4):485-8
"The authors measured the urinary metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in 21 hyperactive boys and 12 matched healthy boys. The hyperactive boys excreted lower amounts of MHPG than control boys. Hyperactive drug responders excreted lower amounts of HVA than control boys and hyperactive nonresponders. Drug responders with normal MHPG excreted low amounts of HVA and those with normal HVA excreted low amounts of MHPG. d-Amphetamine decreased MHPG in all drug responders and HVA in drug responders with normal HVA levels, although it tended to increase HVA in those with low HVA levels. The authors discuss their data in terms of the possible involvement of norepinephrine and dopamine in the etiology of hyperactivity in children." [Abstract]

Shekim WO, Javaid J, Davis JM, Bylund DB.
Urinary MHPG and HVA excretion in boys with attention deficit disorder and hyperactivity treated with d-amphetamine.
Biol Psychiatry 1983 Jun;18(6):707-14
"The authors examined the excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in nine hyperactive and nine control boys admitted to a clinical research center. The hyperactives excreted lower 24 hr MHPG and HVA levels than controls. d-Amphetamine 0.5 mg/kg body weight daily for 2 weeks decreased MHPG and increased HVA. These data replicate the authors' previous findings on MHPG and HVA and on the effect of d-amphetamine in hyperactive children. The data suggest the involvement of norepinephrine and dopamine in the etiology of hyperactivity. It further suggests d-amphetamine may achieve its clinical effects in hyperactivity by inhibiting NE and potentiating DA activity." [Abstract]

Donnelly M, Zametkin AJ, Rapoport JL, Ismond DR, Weingartner H, Lane E, Oliver J, Linnoila M, Potter WZ.
Treatment of childhood hyperactivity with desipramine: plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine levels, and clinical response.
Clin Pharmacol Ther 1986 Jan;39(1):72-81
"Twenty-nine boys with attention deficit disorder/hyperactivity were randomly assigned to receive desipramine (DMI; n = 17) or placebo (n = 12) for 14 days in a noncrossover, double-blind study. There was immediate behavioral improvement with DMI at day 3 that was sustained for 2 weeks; behavioral improvement did not correlate with plasma concentrations of DMI, hydroxy-DMI, or their sum at either days 3 or 14. There were no untoward side effects; there was a drug-induced increase in pulse and diastolic blood pressure. During drug therapy, the urinary excretion of norepinephrine, vanillymandelic acid, and 3-methoxy-4-hydroxyphenylglycol (MHPG) was decreased at both days 3 and 14. The plasma MHPG level was decreased at days 3 and 14 and (standing) plasma NE levels increased at day 14. The decreases in both urinary and plasma MHPG levels showed significant correlations with behavioral improvement during the second week. These data corroborate previous findings on sympathomimetic effects of tricyclic antidepressants in children and support a noradrenergic mechanism in the mediation of drug effects on attention deficit disorder/hyperactivity." [Abstract]

Donnelly M, Rapoport JL, Potter WZ, Oliver J, Keysor CS, Murphy DL.
Fenfluramine and dextroamphetamine treatment of childhood hyperactivity. Clinical and biochemical findings.
Arch Gen Psychiatry 1989 Mar;46(3):205-12
"Twenty boys (mean age, 9 +/- 2 years) with attention deficit disorder with hyperactivity received three weeks each of dextroamphetamine sulfate (0.5 mg/kg/d), fenfluramine hydrochloride (0.6 mg/kg/d increased to 2.0 mg/kg/d), and placebo in a double-blind, random-order, crossover design. Half the boys also met criteria for conduct disorder. Dextroamphetamine produced immediate and marked improvement in disruptive, overactive behaviors. Fenfluramine had no effect on any behavioral measure at either the low or high dosage. Both drugs decreased levels of urinary norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid. Fenfluramine, however, also produced a significant decrease in plasma MHPG levels and a larger decrease in urinary norepinephrine levels. It reduced urinary epinephrine levels as well, an effect opposite to that of dextroamphetamine. These findings suggest that different mechanisms of action are involved in the ability of the two drugs to reduce levels of MHPG and vanillylmandelic acid. Fenfluramine increased plasma prolactin levels and decreased platelet serotonin levels. Despite the structural similarity of the two drugs, some common overall effects on catecholamine metabolism, and similar effects on weight, fenfluramine had none of the motor activity or therapeutic effects of dextroamphetamine." [Abstract]

Zametkin AJ, Hamburger SD.
The effect of methylphenidate on urinary catecholamine excretion in hyperactivity: a partial replication.
Biol Psychiatry 1988 Feb 15;23(4):350-6
"Children with attention deficit disorder with hyperactivity were treated with methylphenidate HCl (0.74 +/- 0.2 mg/kg/day) for 2 weeks in an open trial to assess changes in the urinary excretion of catecholamines and behavior. The purpose of this study was to confirm earlier work that methylphenidate has a distinctly different effect on urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion as compared to earlier studies with dextroamphetamine. Results confirmed the earlier finding that methylphenidate does not significantly change urinary MHPG excretion. No significant relationship was found between behavioral change and any of the urinary catecholamines or metabolites measured." [Abstract]

Zametkin AJ, Karoum F, Linnoila M, Rapoport JL, Brown GL, Chuang LW, Wyatt RJ.
Stimulants, urinary catecholamines, and indoleamines in hyperactivity. A comparison of methylphenidate and dextroamphetamine.
Arch Gen Psychiatry 1985 Mar;42(3):251-5
"Children with attention deficit disorder with hyperactivity were given either methylphenidate hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's effects were distinctly different from those of dextroamphetamine. After methylphenidate administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites was unchanged by either drug. Urinary PEA excretion was not significantly changed after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine. Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic acid excretion. Effects of dextroamphetamine were not tested." [Abstract]

Spivak B, Vered Y, Yoran-Hegesh R, Graff E, Averbuch E, Vinokurow S, Weizman A, Mester R.
The influence of three months of methylphenidate treatment on platelet-poor plasma biogenic amine levels in boys with attention deficit hyperactivity disorder.
Hum Psychopharmacol 2001 Jun;16(4):333-337
"Attention deficit hyperactivity disorder (ADHD) is related to dysregulation in the activity of brain monoamines. The aim of the present study was to assess the impact of three months' methylphenidate (MPH) treatment on platelet-poor plasma (PPP) norepinephrine (NE), dopa and serotonin (5-HT) levels as well as on ADHD symptomatology. Three months of MPH treatment in 16 ADHD boys, aged 11.4 +/- 1.6 years, resulted in a significant reduction in PPP NE levels (p < 0.05). A tendency towards a reduction of PPP 5-HT and dopa levels was detected (p < 0.1 for both). The decrease in PPP biogenic amine levels after three months of MPH treatment was accompanied by a significant reduction in all psychometric characteristics of ADHD. This result indicates the possible role of overactivity of the noradrenergic system in the pathophysiology of ADHD and suggests that the MPH therapeutic action may be related to stimulant-induced inhibitory effect on the noradrenergic system." [Abstract]

Lyseng-Williamson KA, Keating GM.
Extended-release methylphenidate (Ritalin LA).
Drugs 2002;62(15):2251-9; discussion 2260-1
"An extended-release formulation of methylphenidate (Ritalin LA), a CNS stimulant that inhibits dopamine and noradrenaline (norepinephrine) reuptake into presynaptic neurons, has been developed for use in patients with attention deficit/hyperactivity disorder (ADHD). In children with ADHD and healthy male adults, extended-release methylphenidate 20mg was rapidly absorbed and demonstrated two distinct peak plasma concentrations approximately 4 hours apart. The absorption pharmacokinetics of extended-release methylphenidate 20mg, which closely mimics those of immediate-release methylphenidate 10mg given in two doses 4 hours apart, permits once-daily administration. In a 2-week randomised, double-blind, placebo-controlled trial in 134 evaluable children aged 6 to 12 years with ADHD, symptoms improved to a significantly greater extent with extended-release methylphenidate 10 to 40mg once daily than with placebo. Extended-release methylphenidate improved both inattention and hyperactivity symptoms and was effective in children with combined- (inattentive and hyperactive/impulsive) type or predominantly inattentive-type ADHD. In clinical trials, the safety and tolerability profiles of extended-release methylphenidate were consistent with that of the immediate-release formulation." [Abstract]

Stefanatos GA, Wasserstein J.
Attention deficit/hyperactivity disorder as a right hemisphere syndrome. Selective literature review and detailed neuropsychological case studies.
Ann N Y Acad Sci 2001 Jun;931:172-95
"Recent studies of ADHD implicate well-defined neuroanatomical networks and neurochemical pathways in its pathophysiological basis. Considerable attention has focused on the role of anterior and superior frontal regions and portions of the basal ganglia, including the caudate nucleus and globus pallidus. This paper reviews a growing literature suggesting differential involvement of right hemisphere mechanisms specialized for behavioral regulation and attention. Supportive data are drawn from neuropsychology, neuroanatomy, and neurochemistry. In addition, three cases are presented that illustrate the complex role of right hemisphere dysfunction in adult manifestations of ADHD. We suggest that the pleomorphic presentations of ADHD can be understood in terms of a spectrum of disturbances in overlapping neural regions, especially involving frontal and parietal areas of the right hemisphere and their connections to subcortical structures (including the striatum, limbic system and diencephalic nuclei)." [Abstract]

Pliszka SR, McCracken JT, Maas JW.
Catecholamines in attention-deficit hyperactivity disorder: current perspectives.
J Am Acad Child Adolesc Psychiatry 1996 Mar;35(3):264-72
"OBJECTIVE: To provide an update on the "catecholamine hypothesis" of attention-deficit hyperactivity disorder (ADHD). METHOD: Recent work examining the measurement of the norepinephrine, epinephrine, and dopamine systems in ADHD and normal subjects is reviewed and discussed in the context of recent neuroimaging and animal studies. RESULTS: While data clearly indicate a role for all three of the above neurotransmitters in ADHD, a hypothesis suggesting "too much" or "too little" of a single neurotransmitter will no longer suffice. The central norepinephrine system may be dysregulated in ADHD, such that this system does not efficiently "prime" the cortical posterior attention system to external stimuli. Effective mental processing of information involves an anterior "executive" attention system which may depend on dopaminergic input. The peripheral epinephrine system may be a critical factor in the response of individuals with ADHD to stimulant medication. CONCLUSION: A multistage hypothesis is presented which emphasizes the interaction of norepinephrine, epinephrine, and dopamine in modulation of attention and impulse control." [Abstract]

Castellanos FX, Elia J, Kruesi MJ, Gulotta CS, Mefford IN, Potter WZ, Ritchie GF, Rapoport JL.
Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder.
Psychiatry Res 1994 Jun;52(3):305-16
"Cerebrospinal fluid (CSF), plasma, and urinary monoamine metabolites were determined for 29 boys, aged 6-12, with attention-deficit hyperactivity disorder (ADHD). Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolites of serotonin, dopamine, and norepinephrine, respectively, correlated significantly with behavioral measures of aggression and impulsivity/hyperactivity. However, these correlations were in the unexpected direction; for example, CSF 5-HIAA correlated positively with the Brown-Goodwin Lifetime History of Aggression Scale. HVA in CSF was positively correlated with several measures of hyperactivity. The replicability of these findings, as well as possible socioenvironmental effects, and the predictive value of CSF monoamines in prepubertal hyperactivity are the subjects of ongoing study." [Abstract]

Oades RD, Daniels R, Rascher W.
Plasma neuropeptide-Y levels, monoamine metabolism, electrolyte excretion and drinking behavior in children with attention-deficit hyperactivity disorder.
Psychiatry Res 1998 Aug 17;80(2):177-86
"Against a background of (a) increased drinking behavior in children with attention-deficit hyperactivity disorder (ADHD); (b) the parallel between some behaviors associated with ADHD and hypertension; (c) the use of the spontaneously hypertensive rat as a model for ADHD; and (d) similarities in the changes of neuropeptide Y (NPY) and catecholamine in studies of hypertension and drinking, NPY, catecholamines and electrolyte balance were compared in the plasma and urine of healthy children and those with ADHD. Drinking was monitored during 3 h of neuropsychological tests over 2 days in 14 ADHD and nine healthy children. Patients drank four times as much water and showed twice the levels of NPY found in controls. In controls there were positive and in patients there were negative relationships for NPY with drinking and restless behavior. Patients' plasma levels of norepinephrine (NE) and epinephrine were slightly elevated, but urinary levels of NE and the serotonin metabolite were markedly increased. Urinary excretion rates for sodium (not potassium), phosphate and especially calcium were decreased in patients even after covarying for less urine production in the ADHD group. NPY levels were inversely related to calcium excretion and drinking was inversely related to circulating sodium. Increases of drinking and circulating NPY in ADHD children and decreased electrolyte excretion may reflect a common disturbance in metabolic homeostasis." [Abstract]

Oades RD.
Dopamine may be 'hyper' with respect to noradrenaline metabolism, but 'hypo' with respect to serotonin metabolism in children with attention-deficit hyperactivity disorder.
Behav Brain Res 2002 Mar 10;130(1-2):97-102
"Noradrenaline: Hechtman (J Psychiat Neurosci 1994;19:193) argued for a role for frontal dopamine (DA) and noradrenaline (NA) in ADHD, where Oades (Prog Neurobiol 1987;29:365) has described lateralised functional impairments. Mechanisms (e.g. via alpha-2 sites) for stimulating low NA activity in ADHD children (J Am Acad Child Adolesc Psychiatry 1997;36:1688) in order to promote interactions with mesocortical DA have been discussed (J Psychopharmacology 1997;11:151; Psychiatr Res 1994;52:305). We described with indicators of overall transmitter metabolism (monoamines, metabolites in 24 h urine samples (Behav Brain Res 1997;88:95)) significantly lower utilisation ratios (MHPG/NA) in ADHD children with respect to healthy controls. Interestingly, a comparison of between catecholamine levels (DA/NA) showed a correlation with the conditioned blocking measure of selective attention recorded at the time of collection. This measure was negatively associated with blocking in controls. These results are consistent with reports of lower DOPEG and increased DOPAC in ADHD urine (J Child Adolesc Psychopharmacol 1996;6:63) and indicate that the relatively hyperactive DA versus NA systems may have functional consequences. Serotonin: the relevance for ADHD of an association of impulsivity with low serotonin (5-HT) metabolism (Behav Brain Sci 1986;9:319) has long been played down. Yet, some symptoms have been related to CSF measures of the metabolite 5-HIAA, and in particular the HVA/5-HIAA ratio has been reported to correlate with ratings of activity (Psychiatr Res 1994;52:305). We find that while urinary measures of 5-HIAA are somewhat higher, the ratio HVA/5-HIAA is markedly lower in ADHD children versus controls. In these ADHD children 5-HIAA levels were negatively related to d-prime measures in a continuous performance task (CPTax), and the HVA/5-HIAA was negatively associated with conditioned blocking. These results suggest a relatively low DA versus 5-HT activity may have functional consequences, albeit in a subgroup of ADHD. This is consistent with drug-induced prolactin changes reported by Verbaten et al. (Eur Child Adolesc Psychiatry 1999;8:30)." [Abstract]

Kasatikova EV, Larionov NP, Popkova EV, Briazgunov IP.
[Metabolism of catecholamines in children with attention deficit syndrome with hyperactivity]
Vopr Med Khim 2000 Sep-Oct;46(5):455-61
"The aim of research was to study catecholamine excretion peculiarities of the children with attention deficit hyperactivity disorder (ADHD). 25 children at the age of 7-9 years took part in this research. High-pressure liquid chromatography (HPLC) was used for measuring the content of catecholamine. The content of catecholamine was defined in the morning samples of urine. The examination showed, that ADHD children had the basal level of epinephrine and norepinephrine more than the normal control in 3.9 and 5.4 times. After cognitive tests the content of norepinephrine reduced in the ADHD group in 2.1 times in the comparison with normal control. On the contrary content of epinephrine increased in 2.8 times. CONCLUSION: Simpatico-adrenal system hyperactivity (especially it's adrenals component) characterized ADHD children."

Russell VA.
Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder--the spontaneously hypertensive rat.
Behav Brain Res 2002 Mar 10;130(1-2):191-6
"Evidence supports dysfunction of dopaminergic and noradrenergic systems in patients with attention-deficit hyperactivity disorder (ADHD). Noradrenergic and dopaminergic systems exert distinct modulatory actions on the transfer of information through neural circuits that connect functionally distinct cortical areas with separate striatal regions and remain segregated in parallel striato-pallidal-thalamic and striato-substantia nigra pars reticulata-thalamic pathways. Prefrontal cortex performance is maximal at moderate stimulation of postsynaptic dopaminergic and noradrenergic receptors, and is reduced by either higher or lower levels of receptor stimulation. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for ADHD, since they display hyperactivity, impulsivity, poor stability of performance, impaired ability to withhold responses and poorly sustained attention, when compared with their normotensive Wistar-Kyoto (WKY) control rats. Evidence suggests that terminals of mesocortical, mesolimbic and nigrostriatal dopaminergic neurons of SHR release less dopamine in response to electrical stimulation and/or depolarization as a result of exposure to high extracellular K+ concentrations, than WKY. Vesicular storage of dopamine was suggested to be impaired in SHR, causing leakage of dopamine into the cytoplasm and increased d-amphetamine-induced transporter-mediated release. While electrically stimulated release of dopamine appears to be decreased in prefrontal cortex of SHR suggesting hypodopaminergic function, autoreceptor-mediated inhibition of norepinephrine release appears to be impaired in SHR, suggesting that noradrenergic function may be poorly regulated in the prefrontal cortex of the SHR. These findings are consistent with the hypothesis that the behavioral disturbances of ADHD are the result of an imbalance between noradrenergic and dopaminergic systems in the prefrontal cortex, with inhibitory dopaminergic activity being decreased and noradrenergic activity increased relative to controls." [Abstract]

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Recent ADHD and Norepinephrine/Epinephrine Research

1) Schmeichel BE, Zemlan FP, Berridge CW
A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: Potential relevance to attention deficit hyperactivity disorder.
Neuropharmacology. 2012 Jul 11;
Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. This article is part of a Special Issue entitled 'Cognitive Enhancers'. [PubMed Citation] [Order full text from Infotrieve]

2) Minzenberg MJ
Pharmacotherapy for Attention-Deficit/Hyperactivity Disorder: From Cells to Circuits.
Neurotherapeutics. 2012 Jun 21;
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder of childhood and adulthood, with a considerable impact on public health. There is a substantial pharmacopoeia available for safe and effective treatment of ADHD, and newly available agents diversify the treatment options. With the burgeoning scientific literature addressing the genetic, neurochemical, and neural systems basis for this condition, increasing attention is directed at establishing the neural basis for the efficacy of existing treatments. ADHD remains the only highly prevalent, nondegenerative neuropsychiatric disorder for which effective medications remediate the principal cognitive disturbances in concert with clinical efficacy. Therefore, deeper insight into the neural mechanisms of cognitive remediation may serve to advance treatment development not only in ADHD, but across a wide range of neuropsychiatric disorders in which cognitive dysfunction is a cardinal feature and a strong predictor of clinical outcome. To date, all effective medications for ADHD act on 1 or both of the major catecholamine neurotransmitter systems in the brain. These 2 systems, which arise from subcortical nuclei and use norepinephrine (NE) or dopamine (DA) as transmitters, exert strong modulatory effects on widely distributed cortical-subcortical neural circuits, with important effects on cognition, mood, and behavior, in both health and illness. The present review outlines the actions of ADHD medications from subcellular effects to effects on neural systems and cognition in ADHD patients. This is a very active area of investigation at all phases of the translational cycle, and near-term work is poised to firmly link cellular neuropharmacology to large-scale effects, and point the way toward advances in treatment. [PubMed Citation] [Order full text from Infotrieve]

3) Wilson CA, Schade R, Terry AV
Variable prenatal stress results in impairments of sustained attention and inhibitory response control in a 5-choice serial reaction time task in rats.
Neuroscience. 2012 Aug 30;218:126-37.
Rats repeatedly exposed to variable prenatal stress (PNS) exhibit schizophrenia-like behavioral signs such as social withdrawal, elevations in amphetamine-induced locomotor activity, deficits in sensory-motor gating, as well as impairments in memory-related task performance. However, to date there have been no studies designed to test the hypothesis that variable PNS would lead to disruptions in sustained attention and inhibitory response control (i.e., symptoms also commonly observed in schizophrenia and other neuropsychiatric disorders such as attention-deficit hyperactivity disorder). In the current study, the effects of variable PNS in rats were evaluated in fixed and variable stimulus duration (VSD) as well as variable intertrial interval (VITI) versions of a 5-choice serial reaction time task (5C-SRTT). In a separate series of experiments, the glutamate (N-methyl-d-aspartate [NMDA]) antagonist, MK-801 (0.025-0.05mg/kg), and the norepinephrine reuptake inhibitor, atomoxetine (0.30-3.0mg/kg), were administered acutely to assess the sensitivity of PNS subjects to glutamatergic and noradrenergic manipulations. The results indicated that exposure to variable PNS significantly impaired accuracy in the VSD version of the 5C-SRTT and increased premature and timeout responses in the VITI version. In addition, both doses of MK-801 impaired accuracy, increased premature and timeout responses in PNS, but not control subjects. In contrast, atomoxetine decreased premature and timeout responses in both PNS and control subjects in the VITI version of the task and improved accuracy in the PNS subjects. The results suggest that exposure to variable PNS in rats results in impairments of sustained attention and inhibitory response control and that these deficits can be exacerbated by NMDA antagonism and improved by a norepinephrine uptake inhibitor. Collectively, these data further support the premise that variable PNS in rats is a valid model system for the study of neuropsychiatric disorders and their treatment. [PubMed Citation] [Order full text from Infotrieve]

4) Park S, Kim JW, Yang YH, Hong SB, Park MH, Kim BN, Shin MS, Yoo HJ, Cho SC
Possible effect of norepinephrine transporter polymorphisms on methylphenidate-induced changes in neuropsychological function in attention-deficit hyperactivity disorder.
Behav Brain Funct. 2012 May 16;8(1):22.
ABSTRACT: BACKGROUND: Dysregulation of noradrenergic system may play important roles in pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We examined the relationship between polymorphisms in the norepinephrine transporter SLC6A2 genes and attentional performance before and after medication in children with ADHD. METHODS: Fifty-three medication-naive children with ADHD were genotyped and evaluated using the continuous performance test (CPT). After 8-weeks of methylphenidate treatment, these children were evaluated by CPT again. We compared the baseline CPT measures and the post-treatment changes in the CPT measures based on the G1287A and the A-3081T polymorphisms of SLC6A2. RESULTS: There was no significant difference in the baseline CPT measures associated with the G1287A or A-3081T polymorphisms. After medication, however, ADHD subjects with the G/G genotype at the G1287A polymorphism showed a greater decrease in the mean omission error scores (p= 0.005) than subjects with the G/A or A/A genotypes, and subjects with the T allele at the A-3081T polymorphism (T/T or A/T) showed a greater decrease in the mean commission error scores (p= 0.004) than those with the A/A genotypes CONCLUSIONS: Our results provide evidence for the possible role of the G1287A and A-3081T genotypes of SLC6A2 in methylphenidate-induced improvement in attentional performance and support the noradrenergic hypothesis for the pathophysiology of ADHD. [PubMed Citation] [Order full text from Infotrieve]

5) Whelan R, Conrod PJ, Poline JB, Lourdusamy A, Banaschewski T, Barker GJ, Bellgrove MA, Büchel C, Byrne M, Cummins TD, Fauth-Bühler M, Flor H, Gallinat J, Heinz A, Ittermann B, Mann K, Martinot JL, Lalor EC, Lathrop M, Loth E, Nees F, Paus T, Rietschel M, Smolka MN, Spanagel R, Stephens DN, Struve M, Thyreau B, Vollstaedt-Klein S, Robbins TW, Schumann G, Garavan H
Adolescent impulsivity phenotypes characterized by distinct brain networks.
Nat Neurosci. 2012 Apr 29;
The impulsive behavior that is often characteristic of adolescence may reflect underlying neurodevelopmental processes. Moreover, impulsivity is a multi-dimensional construct, and it is plausible that distinct brain networks contribute to its different cognitive, clinical and behavioral aspects. As these networks have not yet been described, we identified distinct cortical and subcortical networks underlying successful inhibitions and inhibition failures in a large sample (n = 1,896) of 14-year-old adolescents. Different networks were associated with drug use (n = 1,593) and attention-deficit hyperactivity disorder symptoms (n = 342). Hypofunctioning of a specific orbitofrontal cortical network was associated with likelihood of initiating drug use in early adolescence. Right inferior frontal activity was related to the speed of the inhibition process (n = 826) and use of illegal substances and associated with genetic variation in a norepinephrine transporter gene (n = 819). Our results indicate that both neural endophenotypes and genetic variation give rise to the various manifestations of impulsive behavior. [PubMed Citation] [Order full text from Infotrieve]

6) Weisler RH, Pandina GJ, Daly EJ, Cooper K, Gassmann-Mayer C
Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder.
CNS Drugs. 2012 May 1;26(5):421-34.
[PubMed Citation] [Order full text from Infotrieve]

7) Economidou D, Theobald DE, Robbins TW, Everitt BJ, Dalley JW
Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens.
Neuropsychopharmacology. 2012 Aug;37(9):2057-66.
Impulsive behavior is a hallmark of several neuropsychiatric disorders (eg, attention-deficit/hyperactivity disorder, ADHD). Although dopamine (DA) and norepinephrine (NE) have a significant role in the modulation of impulsivity their neural loci of action is not well understood. Here, we investigated the effects of the selective NE re-uptake inhibitor atomoxetine (ATO) and the mixed DA/NE re-uptake inhibitor methylphenidate (MPH), both with proven clinical efficacy in ADHD, on the number of premature responses on a five-choice serial reaction time task, an operational measure of impulsivity. Microinfusions of ATO into the shell, but not the core, sub-region of the nucleus accumbens (NAcb) significantly decreased premature responding whereas infusions of MPH in the core, but not the shell, sub-region significantly increased premature responding. However, neither ATO nor MPH significantly altered impulsive behavior when infused into the prelimbic or infralimbic cortices. The opposing effects of ATO and MPH in the NAcb core and shell on impulsivity were unlikely mediated by ancillary effects on behavioral activation as locomotor activity was either unaffected, as in the case of ATO infusions in the core and shell, or increased when MPH was infused into either the core and shell sub-region. These findings indicate an apparently 'opponent' modulation of premature responses by NE and DA in the NAcb shell or core, respectively, and suggest that the symptom clusters of hyperactive-impulsive type ADHD may have distinct neural and neurochemical substrates. [PubMed Citation] [Order full text from Infotrieve]

8) Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ
Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice.
PLoS One. 2012;7(3):e33693.
[PubMed Citation] [Order full text from Infotrieve]

9) Kleijn J, Wiskerke J, Cremers TI, Schoffelmeer AN, Westerink BH, Pattij T
Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation.
Neurochem Int. 2012 Jun;60(8):791-8.
The psychostimulant drug amphetamine is often prescribed to treat Attention-Deficit/Hyperactivity Disorder. The behavioral effects of the psychostimulant drug amphetamine depend on its ability to increase monoamine neurotransmission in brain regions such as the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC). Recent behavioral data suggest that the endocannabinoid system also plays a role in this respect. Here we investigated the role of cannabinoid CB1 receptor activity in amphetamine-induced monoamine release in the NAC and/or mPFC of rats using in vivo microdialysis. Results show that systemic administration of a low, clinically relevant dose of amphetamine (0.5mg/kg) robustly increased dopamine and norepinephrine release (to ?175-350% of baseline values) in the NAC shell and core subregions as well as the ventral and dorsal parts of the mPFC, while moderately enhancing extracellular serotonin levels (to ?135% of baseline value) in the NAC core only. Although systemic administration of the CB1 receptor antagonist SR141716A (0-3mg/kg) alone did not affect monoamine release, it dose-dependently abolished amphetamine-induced dopamine release specifically in the NAC shell. SR141716A did not affect amphetamine-induced norepinephrine or serotonin release in any of the brain regions investigated. Thus, the effects of acute CB1 receptor blockade on amphetamine-induced monoamine transmission were restricted to dopamine, and more specifically to mesolimbic dopamine projections into the NAC shell. This brain region- and monoamine-selective role of CB1 receptors is suggested to subserve the behavioral effects of amphetamine. [PubMed Citation] [Order full text from Infotrieve]

10) Tamburella A, Micale V, Mazzola C, Salomone S, Drago F
The selective norepinephrine reuptake inhibitor atomoxetine counteracts behavioral impairments in trimethyltin-intoxicated rats.
Eur J Pharmacol. 2012 May 15;683(1-3):148-54.
This study was carried out to assess the behavioral effects of the non-psychostimulant drug atomoxetine, in rats prenatally-exposed to the organic compound trimethyltin chloride (TMT) and in spontaneously hypertensive rat (SHR), two rodent models of Attention Deficit/Hyperactivity Disorder (ADHD). At birth, neonatal reflexes (righting, cliff aversion, forelimb placing, forelimb grasping, bar holding and startle) had an earlier onset (i.e. percent of appearance) and completion (maximum appearance, i.e. 100% of the brood exhibiting each reflex) in prenatally TMT-exposed and SHR pups as compared to control groups. Two months after birth, TMT-exposed and SHR rats showed impaired cognitive performances in both the step-through passive avoidance test and the shuttle box active avoidance test. Atomoxetine (1, 3 and 6 mg/kg, i.p.), already at the lowest dose tested, improved learning and memory capacity of prenatally TMT-exposed rats and SHR; while methylphenidate (1, 3 and 6 mg/kg, i.p.), used here as positive control, elicited a significant cognitive enhancing effect only at the higher doses. In the open field test, both TMT-exposed rats and SHR displayed enhanced locomotor activity. Methylphenidate further increased locomotor activity in all groups, whereas atomoxetine reduced the enhanced locomotor activity of TMT-exposed rats and SHR down to the level of controls. These results suggest that prenatal TMT-exposure could be considered as a putative experimental model of ADHD and further support the effectiveness of atomoxetine in the ADHD pharmacotherapy. Furthermore, despite the similar effect of the two drugs on cognitive tasks, they exhibit distinct profiles of activity on locomotion, in ADHD models. [PubMed Citation] [Order full text from Infotrieve]

11) Park MH, Kim JW, Yang YH, Hong SB, Park S, Kang H, Kim BN, Shin MS, Yoo HJ, Cho SC
Regional brain perfusion before and after treatment with methylphenidate may be associated with the G1287A polymorphism of the norepinephrine transporter gene in children with attention-deficit/hyperactivity disorder.
Neurosci Lett. 2012 Apr 18;514(2):159-63.
The noradrenergic system modulates attention and arousal. Dysregulation of the noradrenergic system may be involved in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). This study intended to examine the differences in methylphenidate (MPH) treatment response and pre- and post-treatment cerebral perfusion associated with the G1287A and -3081(A/T) polymorphisms of the norepinephrine transporter (NET) gene in ADHD children. Thirty-seven drug-naïve ADHD children (8.9±1.8 years old, M=32, F=5) were genotyped. Next, baseline single-photon emission computed tomography (SPECT) and clinical assessments were carried out for ADHD subjects. After 8 weeks of MPH treatment, SPECT and clinical assessment were repeated. There were no differences in baseline clinical assessments or cerebral perfusion based on genotype. However, after treatment, ADHD children with the G/G genotype at the G1287A polymorphism showed more improvement in symptoms than children without the G/G genotype as evaluated by the Clinical Global Impressions-Improvement scale (p=0.022). Furthermore, ADHD children with the G/G genotype at the G1287A polymorphism showed hyperperfusion in the right inferior temporal gyrus (p<0.001, uncorrected) and middle temporal gyrus (p=0.001, uncorrected) compared to children without the G/G genotype. Although the results of this study should be interpreted cautiously, they suggest that polymorphisms of the NET gene may contribute to an intermediate phenotype. Further studies should clearly elucidate the relationship between treatment response and functional connectivity in the brain according to this genetic polymorphism. [PubMed Citation] [Order full text from Infotrieve]

12) Howells FM, Stein DJ, Russell VA
Synergistic tonic and phasic activity of the locus coeruleus norepinephrine (LC-NE) arousal system is required for optimal attentional performance.
Metab Brain Dis. 2012 Sep;27(3):267-74.
A certain level of arousal is required for an individual to perform optimally, and the locus coeruleus norepinephrine (LC-NE) system plays a central role in optimizing arousal. Tonic firing of LC-NE neurons needs to be held within a narrow range of 1-3 Hz to facilitate phasic firing of the LC-NE neurons; these two modes of activity act synergistically, to allow the individual to perform attentional tasks optimally. How this information can be applied to further our understanding of psychiatric disorders has not been fully elucidated. Here we propose two models of altered LC-NE activity that result in attentional deficits characteristic of psychiatric disorders: 1) 'hypoaroused' individuals with e.g. attention-deficit/hyperactivity disorder (ADHD) have decreased tonic firing of the LC-NE system, resulting in decreased cortical arousal and poor attentional performance and 2) 'hyperaroused' individuals with e.g. anxiety disorders have increased tonic firing of the LC-NE system, resulting in increased cortical arousal and impaired attentional performance. We argue that hypoarousal (decreased tonic firing of LC-NE neurons) and hyperarousal (increased tonic firing of LC-NE neurons) are suboptimal states in which phasic activity of LC-NE neurons is impeded. To further understand the neurobiology of attentional dysfunction in psychiatric disorders a translational approach that integrates findings on the LC-NE arousal system from animal models and human imaging studies may be useful. [PubMed Citation] [Order full text from Infotrieve]

13) Sutherland SM, Adler LA, Chen C, Smith MD, Feltner DE
An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults with ADHD.
J Clin Psychiatry. 2012 Apr;73(4):445-50.
[PubMed Citation] [Order full text from Infotrieve]

14) Bymaster FP, Golembiowska K, Kowalska M, Choi YK, Tarazi FI
Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB-1020: implications for treatment of attention-deficit hyperactivity disorder.
Synapse. 2012 Jun;66(6):522-32.
We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB-1020 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane HCl). EB-1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC?? values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB-1020 markedly increased NE, and DA concentrations levels in rat prefrontal cortex in vivo with peak increases of 375 and 300%, respectively with the greatest effects on NE, and also increased DA extracellular concentrations in the striatum to 400% of baseline concentrations. Behavioral studies demonstrated that EB-1020 dose-dependently decreased immobility in the mouse tail suspension test of depression to 13% of control levels, and did not stimulate locomotor activity in adult rats in the optimal dose range. EB-1020 dose-dependently inhibited locomotor hyperactivity in juvenile rats lesioned with the neurotoxin 6-hydroxydopamine (100 ?g intracisternally) as neonates; a well-established animal model for attention-deficit hyperactivity disorder (ADHD). These data suggest that EB-1020 mediates its actions by stimulating NE and DA neurotransmission, which are typically impaired in ADHD. [PubMed Citation] [Order full text from Infotrieve]

15) Sengupta SM, Grizenko N, Thakur GA, Bellingham J, DeGuzman R, Robinson S, TerStepanian M, Poloskia A, Shaheen SM, Fortier ME, Choudhry Z, Joober R
Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype.
J Psychiatry Neurosci. 2012 Feb;37(2):129-37.
[PubMed Citation] [Order full text from Infotrieve]

16) Howland RH
The use of dopaminergic and stimulant drugs for the treatment of depression.
J Psychosoc Nurs Ment Health Serv. 2012 Feb;50(2):11-4.
The brain reward system consists of extensive neural pathways that mediate reward behavior such as pleasure and motivation. These pathways may be involved in the development of symptoms such as apathy, anhedonia, and cognitive dysfunction seen in patients with major depression. These pathways are served primarily, although not exclusively, by the chemical neurotransmitter dopamine, which has suggested a therapeutic role for drugs that influence dopamine activity. A small number of clinical trials using various dopaminergic and stimulant drugs for the treatment of major depression and bipolar depression have demonstrated some benefit when combined with standard antidepressant drugs. Based on this work, several ongoing trials are investigating the use of the stimulant drug lisdexamfetamine (Vyvanse®) as an adjunctive treatment for depression. [PubMed Citation] [Order full text from Infotrieve]

17) Abraham AD, Cunningham CL, Lattal KM
Methylphenidate enhances extinction of contextual fear.
Learn Mem. 2012 Feb;19(2):67-72.
Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that received MPH (2.5-10 mg/kg) before an extinction session showed decreased freezing response during extinction, and the effect of the 10 mg/kg dose on freezing persisted to the next day. When MPH (2.5-40 mg/kg) was administered immediately following an extinction session, mice that received MPH showed dose-dependent decreases in freezing during subsequent tests. MPH administered immediately after a 3-min extinction session or 4 h following the first extinction session did not cause significant differences in freezing. Together, these findings demonstrate that MPH can enhance extinction of fear and that this effect is sensitive to dose, time of injection, and duration of the extinction session. Because MPH is widely used in clinical treatments, these experiments suggest that the drug could be used in combination with behavioral therapies for patients with fear disorders. [PubMed Citation] [Order full text from Infotrieve]

18) Childress AC, Sallee FR
The use of lisdexamfetamine dimesylate for the treatment of ADHD.
Expert Rev Neurother. 2012 Jan;12(1):13-26.
ADHD is a common neurobehavioral disorder characterized by significant impairment in attention, hyperactivity and impulsivity. Symptoms begin in childhood and can persist into adulthood. Current data suggest that abnormal functioning of the prefrontal cortex, cortical and subcortical regions of the brain have roles in ADHD. All currently approved drugs used to treat ADHD enhance dopamine and norepinephrine signals in these regions. Lisdexamfetamine dimesylate (LDX) is a long-acting amphetamine prodrug indicated for the treatment of ADHD and has been shown to be effective in children, adolescents and adults. The prodrug properties of LDX make it a desirable treatment because of its long duration of effect, and low intrasubject and intersubject pharmacokinetic variability, and attenuated response on measures of abuse liability when compared with immediate-release amphetamine. However, LDX is still classified as a controlled substance. In this article, the pharmacokinetic parameters and efficacy and safety of LDX are reviewed. [PubMed Citation] [Order full text from Infotrieve]

19) Choi CI, Bae JW, Lee HI, Jang CG, Sohn UD, Lee SY
Determination of atomoxetine metabolites in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study.
J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Feb 15;885-886:103-8.
4-Hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (N-DAT) are major metabolites of atomoxetine, a potent and selective inhibitor of the presynaptic norepinephrine transporter that is used for the treatment of attention deficit/hyperactivity disorder. The pharmacological activity of 4-HAT is similar to that of atomoxetine. We have developed and validated a simple, rapid and sensitive liquid chromatography analytical method with tandem mass spectrometry (LC-MS/MS) for the determination of 4-HAT and N-DAT in human plasma. After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of analytes was performed using a reversed-phase Luna C(18) column (2.0mm×100mm, 3?m particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.5)-methanol (10:90, v/v) and quantified by MS/MS detection in ESI positive ion mode. The flow rate of the mobile phase was 250?L/min and the retention times of 4-HAT, N-DAT and internal standard (IS, metoprolol) were 0.9, 1.0 and 1.0min, respectively. The calibration curves were linear over the range of 0.05-20ng/mL for 4-HAT and 0.1-20ng/mL for N-DAT. The lower limits of quantification, using 200?L human plasma, were 0.05 and 0.1ng/mL for 4-HAT and N-DAT, respectively. The mean accuracy and precision for intra- and inter-day validation of 4-HAT and N-DAT were both within the acceptable limits. This LC-MS/MS method showed improved sensitivity for quantification of the two main metabolites of atomoxetine in human plasma compared with previously described analytical methods. The validated method was successfully applied to a pharmacokinetic study in humans. [PubMed Citation] [Order full text from Infotrieve]

20) Prommer E
Methylphenidate: Established and Expanding Roles in Symptom Management.
Am J Hosp Palliat Care. 2011 Dec 4;
Methylphenidate is a psychostimulant originally used for the treatment of attention-deficit disorder. Methylphenidate inhibits neuronal neurotransmitter transporters involved in the uptake of dopamine and norepinephrine at the level of the synapse. Inhibition of these transmitter transporters leads to increased concentrations of dopamine and norepinephrine in the synapse, which results in increasing alertness. The stimulant effect of methylphenidate has been used for the treatment of major depression, poststroke depression, cognitive enhancement in patients with brain tumors, neurodegenerative disorders, HIV disease, fatigue, and as a treatment for delirium and sedation associated with opioid use. Other areas where methylphenidate has been evaluated include gait disorders in the elderly individuals and the treatment of apathy in dementia. Analgesic effects have been demonstrated in preclinical models but true analgesic effects remain to be proven in humans. This article reviews the current use of methylphenidate for symptom management with a critical look at the evidence base for its efficacy in the conditions described. [PubMed Citation] [Order full text from Infotrieve]