Effects of Stimulant Medication on Growth Rates Across 3 Years in the MTA Follow-up

Swanson, James M.; Elliott, Glen R.; Greenhill, Laurence L.; Wigal, Timothy; Arnold, L. Eugene; Vitiello, Benedetto; Hechtman, Lily; Epstein, Jeffery N.; Pelham, William E.; Abikoff, Howard; Newcorn, Jeffrey H.; Molina, Brooke S. G.; Hinshaw, Stephen P.; Wells, Karen C.; Hoza, Betsy; Jensen, Peter S.; Gibbons, Robert D.; Hur, Kwan; Stehli, Annamarie; Davies, Mark; March, John S.; Conners, C. Keith; Caron, Mark D.; Volkow, Nora D.

doi:10.1097/chi.0b013e3180686d7e

Cited by 274 publications

(217 citation statements)

References 38 publications

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“…These results are consistent with, and may provide an insight into potential neuroendocrine mechanisms that underlie delayed growth and maturation associated with the use of one of the most widely prescribed medications in children (21). The fact that effects were transient and that no permanent deficits were found in the monkey model alleviates concerns about the clinical use of MPH in youth.…”

Section: Discussionsupporting

confidence: 76%

Pubertal delay in male nonhuman primates (Macaca mulatta) treated with methylphenidate

Mattison

Plant

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Juvenile male rhesus monkeys treated with methylphenidate hydrochloride (MPH) to evaluate genetic and behavioral toxicity were observed after 14 mo of treatment to have delayed pubertal progression with impaired testicular descent and reduced testicular volume. Further evaluation of animals dosed orally twice a day with (i) 0.5 mL/kg of vehicle (n = 10), (ii) 0.15 mg/kg of MPH increased to 2.5 mg/kg (low dose, n = 10), or (iii) 1.5 mg/kg of MPH increased to 12.5 mg/kg (high dose, n = 10) for a total of 40 mo revealed that testicular volume was significantly reduced (P < 0.05) at months 15 to 19 and month 27. Testicular descent was significantly delayed (P < 0.05) in the high-dose group. Significantly lower serum testosterone levels were detected in both the low-(P = 0.0017) and high-dose (P = 0.0011) animals through month 33 of treatment. Although serum inhibin B levels were increased overall in low-dose animals (P = 0.0328), differences between groups disappeared by the end of the study. Our findings indicate that MPH administration, beginning before puberty, and which produced clinically relevant blood levels of the drug, impaired pubertal testicular development until ∼5 y of age. It was not possible to resolve whether MPH delayed the initiation of the onset of puberty or reduced the early tempo of the developmental process. Regardless, deficits in testicular volume and hormone secretion disappeared over the 40-mo observation period, suggesting that the impact of MPH on puberty is not permanent.attention deficit hyperactivity disorder | developmental delay | male puberty D uring studies in the rhesus monkey to address the genetic and behavioral toxicity of methylphenidate hydrochloride (MPH) in the nonhuman primate (NHP) (1), it was noted that testicular growth was retarded and testicular descent was delayed in animals treated with a high dose of MPH. As in boys, an acceleration of testicular growth in the rhesus monkey, which generally occurs between 3 and 4 y of age, is a reliable somatic marker of the initiation of puberty (2, 3). Puberty in both man and the monkey is triggered by the reemergence of a robust pattern of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) release that activates the pituitary-gonadal axis at the end of the juvenile phase of development (2, 3). Interestingly, in higher primates the GnRH drive to pituitary gonadotropin secretion is also observed during infancy, but throughout juvenile development (and during childhood in man) this mode of hypothalamic GnRH release is held in check resulting in a relatively hypogonadotropic state that guarantees the quiescence of the prepubertal primate gonad (2, 3). Thus, the rhesus macaque is a particularly good model for human puberty.Potential modulators of the pubertal process, such as MPH, may be conceptualized to influence either the timing of the onset of puberty or the tempo at which this developmental event unfolds once initiated. To examine this issue in the monkey, the findings on the effect of MPH on the reproductive axis ob...

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Section: Discussionsupporting

confidence: 76%

Pubertal delay in male nonhuman primates (Macaca mulatta) treated with methylphenidate

Mattison

Plant

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The SWAN scale differs from other scales in its definition of items and in its scoring system, which give a closer approximation to a normal distribution for each item and of summary scores of overall ADHD and its two domains (Inattention and Hyperactivity-Impulsivity) in the general population than does any other ADHD scale that evaluates psychopathology. 39 In addition, the heritability of the SWAN scale has been shown. 39 Consistency scores were estimated for each interview, using a scale from 1 (unreliable) to 10 (fully reliable), according to the concordance between two questions.…”

Section: Pharmacogenetic Studymentioning

confidence: 99%

“…39 In addition, the heritability of the SWAN scale has been shown. 39 Consistency scores were estimated for each interview, using a scale from 1 (unreliable) to 10 (fully reliable), according to the concordance between two questions. A full description of ascertainment and clinical diagnostic strategies of the US1 sample is presented elsewhere.…”

Section: Pharmacogenetic Studymentioning

confidence: 99%

“…39 By truncating the SWAN ratings, the standard ratings of symptom severity (just weaknesses) can be captured. The SWAN scale differs from other scales in its definition of items and in its scoring system, which give a closer approximation to a normal distribution for each item and of summary scores of overall ADHD and its two domains (Inattention and Hyperactivity-Impulsivity) in the general population than does any other ADHD scale that evaluates psychopathology.…”

Section: Pharmacogenetic Studymentioning

confidence: 99%

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A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication

et al. 2010

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Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a familybased design. Family-and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n = 6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

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“…Indeed, MPH and AMP are abused and can result in addiction (Volkow and Swanson, 2003). Another clinical concern has been the potential adverse effects of stimulant medications on physical growth (Swanson et al, 2007). However, resolution of these critical clinical issues about stimulant medications has been difficult to address directly in humans because of ethical and practical considerations.…”

mentioning

confidence: 99%

Long-Term Safety of Stimulant Use for ADHD: Findings from Nonhuman Primates

Volkow

2012

Neuropsychopharmacol

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Effects of Stimulant Medication on Growth Rates Across 3 Years in the MTA Follow-up

Cited by 274 publications

References 38 publications

Pubertal delay in male nonhuman primates (Macaca mulatta) treated with methylphenidate

Pubertal delay in male nonhuman primates (Macaca mulatta) treated with methylphenidate

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication

Long-Term Safety of Stimulant Use for ADHD: Findings from Nonhuman Primates

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