Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder

May combine two claims.

The correlation between methylphenidate-induced dopamine increases in ventral striatum and improvement in inattention was significant for measures obtained after long-term treatment but not for those obtained before treatment initiation.

“The ROI analysis revealed that the correlations between improvement in clinical symptoms with oral MP treatment (before treatment initiation vs after long-term treatment) and the DA increases elicited by intravenous MP (quantified as decreases in D2/D3 receptor availability) were significant for the measures obtained after long-term treatment but not with those obtained before treatment initiation”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

SPM analysis showed the same trend for higher D2/D3 receptor availability before treatment than after long-term treatment, but the effect was not significant when corrected for multiple comparisons with familywise error.

“The SPM analysis showed the same trend (p < 0.05 uncorrected), although the effect was not significant when corrected for multiple comparisons with familywise error (pFWE-CORR > 0.05).”

May combine two claims.

Clinical treatment with oral methylphenidate over 12 months significantly reduced ADHD symptoms, with all CAARS scales higher before treatment initiation than after 1 year of treatment.

“The prospective clinical treatment with MP was associated with a significant decrease in average ratings of ADHD symptoms. All scales of the CAARS were significantly higher before treatment initiation than after 1 year of treatment with the titrated regimen or oral MP (Table 1).”

Probably not a substantial claim: may not pass S3 (load-bearing).

None of these findings was affected when Hamilton Depression and Anxiety scores were used as covariates.

“None of these findings was affected when we used as covariates the scores on the Hamilton's Depression and Anxiety scales.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Baseline measures of D2/D3 receptor availability in putamen (naive condition) were higher than those reported in another group of naive ADHD adults (3.64 vs 3.44) but similar to the controls from that study (3.63).

“Baseline measures of D2/D3 receptor availability in putamen (naive condition) were higher than those we reported in another group of naive ADHD adults (3.64 vs 3.44) but similar to the controls from that study (3.63) (Volkow et al., 2007).”

• cites Volkow et al., 2007Not checked yet

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May combine two claims.

Long-term treatment with methylphenidate decreased methylphenidate-induced dopamine increases in striatum but not in cortex.

“Long-term treatment with MP decreased MP-induced DA increases in striatum but not in cortex.”

May combine two claims.

Baseline measures of D2/D3 receptor availability in dorsal striatum (placebo measures) were lower after long-term treatment with oral methylphenidate than before treatment, but SPM did not corroborate this unless significance was decreased to puncorr < 0.05.

“The ROI analysis revealed that baseline measures of D2/D3 receptor availability in dorsal striatum (placebo measures) were lower after long-term treatment with oral MP than before treatment (treatment-naive), but SPM did not corroborate this unless we decreased significance to puncorr < 0.05.”

Classified as probably not a substantial claim.

Disrupted dopamine neurotransmission has been implicated in the pathophysiology of ADHD.

“Disrupted dopamine (DA) neurotransmission has been implicated in its pathophysiology (Volkow et al., 2007; Prince, 2008).”

• cites Volkow et al., 2007Not checked yet

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• cites Prince, 2008Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Methylphenidate increases dopamine by blocking dopamine transporters (DATs).

“MP increases DA by blocking dopamine transporters (DATs) and amphetamine by releasing DA from the terminal using the DAT as carrier (Kuczenski and Segal, 1997).”

• cites Kuczenski and Segal, 1997Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Methylphenidate and amphetamine are the primary medications used to treat ADHD.

“The stimulants drugs methylphenidate (MP) and amphetamine are the primary medications used to treat ADHD (Ilgenli et al., 2007; Rubia et al., 2009)”

• cites Ilgenli et al., 2007Not checked yet

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• cites Rubia et al., 2009Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

All images were carefully inspected to ensure whole-brain coverage and exclude images with potential artifacts.

“All images were carefully inspected to ensure whole-brain coverage and exclude images with potential artifacts.”

May combine two claims.

Because only 10% of adults in the U.S. population meeting ADHD criteria are treated at any given time, the exclusion criteria did not pose a selection bias.

“Because it is estimated that only 10% of adults in the U.S. population meeting the criteria for ADHD are treated at any given time (Kessler et al., 2006), this exclusion criteria did not pose a selection bias.”

• cites Kessler et al., 2006Not checked yet

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May combine two claims.

Dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD.

“Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD.”

Classified as probably not a substantial claim.

Findings with the ROI analysis were considered significant only if corroborated with Statistical Parametric Mapping (SPM).

“Findings with the ROI analysis were considered significant only if corroborated with Statistical Parametric Mapping (SPM) (Friston et al., 1995).”

• cites Friston et al., 1995Not checked yet

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Classified as probably not a substantial claim.

To control for the contribution of depression and anxiety on methylphenidate-induced dopamine changes, Hamilton scores were included as covariates in the analyses.

“To control for the contribution of depression and anxiety on MP-induced DA changes, we included the Hamilton scores as covariates in the analyses.”

Classified as probably not a substantial claim.

Evidence was required from each subject's history that some symptoms of ADHD were present in childhood (before age 7 years).

“In addition, evidence was required from each subject's history that some symptoms of ADHD were present in childhood (before age 7 years) even when the diagnosis was not made until adulthood.”

Classified as probably not a substantial claim. May combine two claims.

The PET scans for the long-term treatment condition were conducted 24-48 h after the last clinical dose of methylphenidate to allow levels to dissipate, and plasma methylphenidate levels were measured to ensure they were nondetectable.

“The PET scans for the long-term treatment condition were conducted 24–48 h after the last clinical dose of MP to allow for the levels of MP from the final dose to dissipate before the PET study (Modi et al., 2000). To corroborate this, we measured plasma MP levels before intravenous injection of MP to ensure that they were nondetectable.”

• cites Modi et al., 2000Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Urine drug screens were obtained on all subjects the day of the PET scan to check for psychoactive drug use.

“Urine drug screens were obtained on all subjects the day of the PET scan to check for psychoactive drug use.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Correlations were restricted to three subscales to limit the number of analyses.

“We restricted correlations to three subscales to limit the number of analyses”

Probably not a substantial claim: may not pass S3 (load-bearing).

Participants underwent urine drug toxicological tests to ensure absence of drug use both at screening and before the PET scan evaluations.

“To ascertain past history of substance abuse, participants were asked about present or past substance abuse and underwent urine drug toxicological tests to ensure absence of drug use both at the time of screening and before the PET scan evaluations.”

Classified as probably not a substantial claim.

At least two clinicians interviewed the patients to ensure that they met DSM-IV diagnostic criteria for ADHD.

“At least two clinicians interviewed the patients to ensure that they met the Diagnostic and Statistical Manual IV (DSM-IV) diagnostic criteria for ADHD”

Classified as probably not a substantial claim. May combine two claims.

[11C]raclopride is a dopamine D2/D3 receptor radioligand whose specific binding is sensitive to competition by endogenous dopamine.

“The DA increases to the acute MP challenge were assessed using positron emission tomography (PET) with [ 11C]raclopride (DA D2/D3 receptor radioligand whose specific binding is sensitive to competition by endogenous DA) (Dewey et al., 1993).”

• cites Dewey et al., 1993Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Increasing evidence suggests that a reward and motivation deficit may be of equal importance to an attention deficit in ADHD.

“Historically, the core feature of ADHD has been characterized as one of an attention deficit, but increasing evidence suggests that a reward and motivation deficit may be of equal importance (Haenlein and Caul, 1987; Sonuga-Barke, 2003; Tripp and Wickens, 2008; Castellanos, 2009; Volkow et al., 2009).”

• cites Haenlein and Caul, 1987 sourceNot checked yet

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• cites Sonuga-Barke, 2003Not checked yet

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• cites Tripp and Wickens, 2008Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The study used a single blind design in which subjects were blind to the drugs received.

“The study used a single blind design (subjects were blind to the drugs received).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Prefrontal regions express low dopamine transporter levels.

“Although prefrontal regions expresses low DAT levels (Sesack et al., 1998), MP also blocks norepinephrine transporters (Hannestad et al., 2010), which in prefrontal cortex contribute to DA reuptake and mediate DA increases (Carboni et al., 1990; Morón et al., 2002).”

• cites Sesack et al., 1998 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A key component of the dopamine-deficit theory of ADHD proposes that methylphenidate treatment enhances dopamine in the prefrontal cortex and this contributes to its therapeutic effects.

“A key component of the DA-deficit theory of ADHD proposes that MP treatment enhances DA in the prefrontal cortex and this contributes to its therapeutic effects (Arnsten, 2009), and fMRI studies support this (Bush et al., 2008).”

• cites Arnsten, 2009Not checked yet

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• cites Bush et al., 2008Not checked yet

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May combine two claims.

The attenuation in striatum but not cortical regions suggests changes in dopamine autoreceptor sensitivity and/or dopamine transporter upregulation.

“Because the attenuation was in striatum and not in cortical regions, this suggests that they reflect changes in DA autoreceptor sensitivity and/or DAT upregulation because cortical DA projections are much less sensitive to regulation by DA autoreceptors or DAT (Lammel et al., 2008).”

• cites Lammel et al., 2008Not checked yet

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May combine two claims.

The reductions in D2/D3 receptor availability in prefrontal and temporal cortices are reliable effects, based on consistency across both assessments and high statistical significance.

“Although the accuracy of [11C]raclopride to measure DA changes in cortical regions is limited (Egerton et al., 2009), the consistency across both assessments and the high level of statistical significance suggest that these are reliable effects.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Oral methylphenidate (0.63 mg/kg) increased dopamine in prefrontal and temporal cortices in controls.

“Moreover, a previous study showed that oral MP (0.63 mg/kg) increased DA in prefrontal and temporal cortices in controls using [ 11C]FLB 457 [(S)-5-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide monohydrobromide] (Montgomery et al., 2007).”

• cites Montgomery et al., 2007Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Methylphenidate blocks norepinephrine transporters.

“Although prefrontal regions expresses low DAT levels (Sesack et al., 1998), MP also blocks norepinephrine transporters (Hannestad et al., 2010), which in prefrontal cortex contribute to DA reuptake and mediate DA increases (Carboni et al., 1990; Morón et al., 2002).”

• cites Hannestad et al., 2010Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

In adolescents with ADHD, decreased dopamine synthesis in the nucleus accumbens is correlated with symptoms of inattention.

“In ADHD, the decreased DA synthesis of adolescents in nucleus accumbens (located in VS) was also correlated with symptoms of inattention (Forssberg et al., 2006), suggesting that our findings may also pertain to adolescents with ADHD.”

• cites Forssberg et al., 2006Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There is evidence of the involvement of temporal cortical regions in ADHD and of their sensitivity to methylphenidate.

“Although much less investigated, there is also evidence of the involvement of temporal cortical regions in ADHD (Kobel et al., 2010) and on their sensitivity to MP (Rubia et al., 2009).”

• cites Kobel et al., 2010Not checked yet

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• cites Rubia et al., 2009Not checked yet

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May combine two claims.

The reductions in dopamine increases are likely to reflect neuroplasticity effects of chronic methylphenidate treatment rather than natural decline.

“These reductions are likely to reflect neuroplasticity effects of chronic MP treatment rather than natural decline because, in healthy controls, DA increases induced by amphetamine were higher (not lower) when subjects were retested 12 months later without any therapeutic intervention (Boileau et al., 2006).”

• cites Boileau et al., 2006Not checked yet

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May combine two claims.

Methylphenidate could ameliorate inattention by both enhancing saliency (through effects on the ventral striatum) and enhancing the executive components of attention that are mediated through prefrontal regions.

“MP could ameliorate inattention by both enhancing saliency (through effects on VS) and enhancing the executive components of attention that are mediated through prefrontal regions (including cingulate gyrus) (Fan et al., 2005).”

• cites Fan et al., 2005Not checked yet

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May combine two claims.

Methylphenidate, by increasing dopamine in the ventral striatum, enhances the saliency of the task, thus improving attention in ADHD.

“we had proposed that MP, by increasing DA in VS (central brain region for motivation and reward; Wise, 2002) would enhance the saliency of the task, thus improving attention in ADHD (Volkow et al., 2001, 2004), and our current finding of a correlation between MP-induced DA increases in VS and reductions in inattention support this.”

• cites Wise, 2002Not checked yet

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• cites Volkow et al., 2001 sourceNot checked yet

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• cites Volkow et al., 2004Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Dopamine increases in prefrontal and temporal cortices have been reported with drug challenges (tetrahydrocannabinol and methamphetamine) using [11C]raclopride.

“Indeed, others have reported DA increases in prefrontal and temporal cortices with drug challenges (tetrahydrocannabinol and methamphetamine) using [ 11C]raclopride (Piccini et al., 2003; Stokes et al., 2010).”

• cites Piccini et al., 2003Not checked yet

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• cites Stokes et al., 2010Not checked yet

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May combine two claims.

In adults with ADHD, dopamine markers in the ventral striatum are associated with symptoms of inattention and reduced trait motivation.

“They are also consistent with previous findings of an association between DA markers in the VS and symptoms of inattention and with reduced scores in a trait measure of motivation in adults with ADHD (Volkow et al., 2011).”

• cites Volkow et al., 2011Not checked yet

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May combine two claims.

In prefrontal cortex, norepinephrine transporters contribute to dopamine reuptake and mediate dopamine increases.

“Although prefrontal regions expresses low DAT levels (Sesack et al., 1998), MP also blocks norepinephrine transporters (Hannestad et al., 2010), which in prefrontal cortex contribute to DA reuptake and mediate DA increases (Carboni et al., 1990; Morón et al., 2002).”

• cites Carboni et al., 1990Not checked yet

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• cites Morón et al., 2002 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The study cannot determine whether the dampening of dopamine-enhancing effects of methylphenidate after long-term treatment is associated with tolerance to clinical efficacy, whether it is long lasting or dissipates promptly.

“We show dampening of the DA-enhancing effects of MP after long-term treatment, but we cannot determine whether this is associated with tolerance to clinical efficacy, whether it is long lasting or dissipates promptly.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The study did not obtain measures of motivation, which would have allowed testing whether dopamine increases in the ventral striatum were associated with increased motivation while on clinical treatment.

“In our study, we did not obtain measures of motivation, which would have allowed us to test whether DA increases in VS were associated with increased motivation while on clinical treatment.”

May combine two claims.

The [11C]raclopride method is best suited for regions with high D2/D3 receptor density, such as striatum, and much less sensitive to cortical regions, which renders the cortical findings preliminary.

“The [ 11C]raclopride method is best suited for regions with high D2/D3 receptor density, such as striatum, and much less sensitive to cortical regions, which renders our cortical findings as preliminary.”

May combine two claims.

Using ROIs obtained directly from [11C]raclopride images rather than MRIs is unlikely to have influenced the findings, because measures of D2/D3 receptor availability obtained using ROIs selected directly from [11C]raclopride images do not differ from those selected from the subject's MRIs.

“ROIs were obtained directly from the [ 11C]raclopride images and not from MRIs but, because measures of D2/D3 receptor availability obtained using ROIs selected directly from [ 11C]raclopride images do not differ from those selected from the subject's MRIs (Wang et al., 1996), this is unlikely to have influenced our findings.”

• cites Wang et al., 1996Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

These differences are likely to reflect intersubject variability as well as noncontrolled variables that influence D2/D3 receptor availability.

“These differences are likely to reflect intersubject variability as well as noncontrolled variables that influence D2/D3 receptor availability (i.e., sleep deprivation) (Volkow et al., 2008).”

• cites Volkow et al., 2008Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Because of ethical reasons, the study did not use a group of untreated ADHD controls to rule out the possibility that the attenuation reflects an age-related decline.

“Because of ethical reasons, we did not use a group of untreated ADHD controls to rule out the possibility that the attenuation reflects an age-related decline.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Changes in [11C]raclopride binding are related to extracellular dopamine, but the relationship with synaptic dopamine is not completely understood.

“Changes in [ 11C]raclopride binding are related to extracellular DA, but the relationship with synaptic DA is not completely understood (Gjedde et al., 2005).”

• cites Gjedde et al., 2005Not checked yet

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