Cardiovascular Effects of Atomoxetine in Children, Adolescents, and Adults

Wernicke, Joachim; Faries, Douglas E.; Girod, Donald A.; Brown, Jess; Gao, Haitao; Kelsey, Douglas K.; Quintana, Humberto; Lipetz, Robert S.; Michelson, David; Heiligenstein, John H.

doi:10.2165/00002018-200326100-00006

Cited by 168 publications

(132 citation statements)

References 11 publications

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“…The significant change in HR (þ10.3 bpm) during the study was largely accounted for by the 8.6-bpm increase in HR during ATMX monotherapy, consistent with prior reports of HR increase during treatment with ATMX (Wernicke et al 2003). In their one small prior study of combined ATMX and OROS MPH, Carlson et al (2007) reported a 5-bpm increase in HR.…”

Section: Hammerness Et Alsupporting

confidence: 84%

“…Cardiovascular changes observed during combination therapy were consistent with increases in blood pressure documented in children with ADHD treated with stimulants (Findling et al 2005;Wilens et al 2005;Donner et al 2007) and ATMX (Michelson et al 2001;Wernicke et al 2003). In addition, there were no serious cardiovascular AEs during combination therapy, and no subject discontinued due to cardiovascular AEs.…”

Section: Hammerness Et Alsupporting

confidence: 73%

“…Conversely, SBP did not significantly increase in the short-term end point, but was significantly increased at the 6-month longer-term end point. Analysis of cardiovascular effects of ATMX suggests that short-term blood pressure increases may stabilize over time (Wernicke et al 2003).…”

Section: Hammerness Et Almentioning

confidence: 99%

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An Open Study of Adjunct OROS-Methylphenidate in Children Who Are Atomoxetine Partial Responders: II. Tolerability and Pharmacokinetics

Hammerness

Georgiopoulos

Doyle

et al. 2009

Journal of Child and Adolescent Psychopharmacology

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Objective: The aim of this study was to evaluate the tolerability of adding OROS methylphenidate (MPH) to children who are partial responders to atomoxetine (ATMX) in the treatment of attention-deficit=hyperactivity disorder (ADHD). Methods: This was a two-phase, 7-week, open study in children aged 6-17 years. Phase 1 initiated ATMX for a minimum of 4 weeks. Phase 2 entered partial responders to ATMX and added OROS MPH to their regimen. Safety was assessed using blood pressure and heart rate measurements, electrocardiogram readings, AEs, laboratories, and ATMX levels. Results: Fifty subjects who were partial responders to ATMX received the combination therapy, with 41 subjects completing the entire protocol. As reported elsewhere , OROS MPH added to partial responders of ATMX was accompanied by a 40% reduction in the ADHD rating scale score and improvements in executive functioning. However, the combination of ATMX plus OROS MPH was associated with greater rates of insomnia, irritability, and loss of appetite compared to ATMX alone. A small significant increase in diastolic blood pressure was observed during adjunctive OROS MPH, with no clinically meaningful changes in electrocardiogram (ECG) parameters during the study. ATMX levels and liver function tests did not significantly change during the combination treatment. Conclusion: Adjunct OROS MPH in ATMX partial responders yielded an additive adverse effect burden in this short-term study. Further controlled research with larger samples of children is warranted.

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Section: Hammerness Et Alsupporting

confidence: 84%

Section: Hammerness Et Alsupporting

confidence: 73%

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An Open Study of Adjunct OROS-Methylphenidate in Children Who Are Atomoxetine Partial Responders: II. Tolerability and Pharmacokinetics

Hammerness

Georgiopoulos

Doyle

et al. 2009

Journal of Child and Adolescent Psychopharmacology

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“…On this background, there is concern that this family of drugs could worsen or even induce hypertension. 4 Indeed, blockade of norepinephrine reuptake would be expected to increase neurotransmitter concentrations in the neuro-effector junction, and in the periphery this effect would lead to a pressor response. This mechanism, however, seems to be counteracted by a central sympatholytic action through activation of ␣-2 adrenoreceptors (a "clonidine-like" effect).…”

mentioning

confidence: 99%

Norepinephrine Transporter Blockade With Atomoxetine Induces Hypertension in Patients With Impaired Autonomic Function

et al. 2007

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Abstract-Atomoxetine, a selective norepinephrine transporter blocker, could increase blood pressure by elevating norepinephrine concentration in peripheral sympathetic neurons. This effect may be masked in healthy subjects by central sympatholytic mechanisms. To test this hypothesis we studied the pressor effect of 18 mg of atomoxetine (pediatric dose) in 21 patients with damage of the central (10 subjects) and peripheral (11 subjects) autonomic nervous system. Atomoxetine was administered in a randomized, crossover, placebo-controlled fashion, and blood pressure and heart rate were measured at baseline and for 60 minutes after drug intake. Atomoxetine acutely increased seated and standing systolic blood pressure in patients with central autonomic failure by 54Ϯ26 (meanϮstandard deviation; Pϭ0.004) and 45Ϯ23 mm Hg (Pϭ0.016), respectively, as compared with placebo. At the end of the observation period the mean seated systolic blood pressure in the atomoxetine group was in the hypertensive range (149Ϯ26, range 113 to 209 mm Hg). However, in patients with peripheral autonomic failure, atomoxetine did not elicit a pressor response; seated and standing systolic blood pressure increased by 4Ϯ18 mm Hg (Pϭ0.695) and 0.6Ϯ8 mm Hg (Pϭ0.546) with atomoxetine as compared with placebo. In conclusion, atomoxetine induces a dramatic increase in blood pressure in patients with central autonomic failure even at very low doses. These findings suggest that a functional central sympatholytic pathway is essential to avoid hypertension in patients treated with this drug. Caution should be exercised when this medication is used in patients with milder form of autonomic impairment. Key Words: atomoxetine Ⅲ norepinephrine transporter protein Ⅲ hypertension Ⅲ autonomic nervous system diseases Ⅲ multiple system atrophy

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“…Under treatment, the mean heart rate and pulse rate increase as a consequence of the mechanism of action and its impact on the sympathetic and parasympathetic systems. The increases in blood pressure and pulse tends to occur early in therapy, stabilise, and then return toward baseline upon drug discontinuation (Wernicke et al, 2003). Because of the relationship between these effects and the mechnism of action of the drug on ADHD, elevation of pulse rate was used as a marker of pharmacological action.…”

Section: Introductionmentioning

confidence: 99%

A Bayesian Approach for Dose-Escalation in a Phase I Clinical Trial Incorporating Pharmacodynamic Endpoints

Whitehead

Zhou

Ledent

et al. 2007

Journal of Biopharmaceutical Statistics

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Bayesian decision procedures have already been proposed for and implemented in phase I dose-escalation studies in healthy volunteers. The procedures have been based on pharmacokinetic responses reflecting the concentration of the drug in blood plasma and are conducted to learn about the dose-response relationship while avoiding excessive concentrations.However, in many dose-escalation studies, pharmacodynamic endpoints such as heart rate or blood pressure are observed, and it is these that should be used to control dose-escalation. These endpoints introduce additional complexity into the modelling of the problem relative to pharmacokinetic responses. Firstly, there are responses available following placebo administrations.Secondly, the pharmacodynamic responses are related directly to measurable plasma concentrations, which in turn are related to dose. Motivated by experience of data from a real study conducted in a conventional manner, this paper presents and evaluates a Bayesian procedure devised for the simultaneous monitoring of pharmacodynamic and pharmacokinetic responses. Account is also taken of the incidence of adverse events. Following logarithmic transformations, a linear model is used to relate dose to the pharmacokinetic endpoint and a quadratic model to relate the latter to the pharmacodynamic endpoint. A logistic model is used to relate the pharmacokinetic endpoint to the risk of an adverse event.

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Cardiovascular Effects of Atomoxetine in Children, Adolescents, and Adults

Cited by 168 publications

References 11 publications

An Open Study of Adjunct OROS-Methylphenidate in Children Who Are Atomoxetine Partial Responders: II. Tolerability and Pharmacokinetics

An Open Study of Adjunct OROS-Methylphenidate in Children Who Are Atomoxetine Partial Responders: II. Tolerability and Pharmacokinetics

Norepinephrine Transporter Blockade With Atomoxetine Induces Hypertension in Patients With Impaired Autonomic Function

A Bayesian Approach for Dose-Escalation in a Phase I Clinical Trial Incorporating Pharmacodynamic Endpoints

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