MPH Part 4 - Responding, Genetic Influences

“Response” means that a medication improves ADHD symptoms to a specified minimum degree. “Nonresponse,” therefore, does not mean that there is no effect at all. There is no standard definition. Furthermore, some of the responses observed in studies were due to placebo effects. Parents, teachers, and tests often assessed the effect differently.

In studies, a large proportion of people with ADHD responded to MPH, as well as to amphetamine medications. True nonresponders to both stimulants were rare when both active ingredients were carefully tested across a wide range of doses. When both were tested sequentially, the proportion of responders increased significantly. A lack of response to one active ingredient did not imply a lack of response to the other. Even a lack of response to MPH did not rule out a response to atomoxetine. Therefore, if MPH is not sufficiently effective, it is recommended to try an amphetamine medication.

According to ADxS, a dose that is too low can cause an apparent lack of response. In one study, increasing the dose in children who had not responded to a low dose often improved their attention in class. Body weight did not predict either the optimal dose or the response.

Numerous characteristics were examined as potential predictors, including subtype, age, baseline severity, comorbidities, intelligence, EEG, imaging, blood test results, and genetic variants. Indications of a better response included, for example, a good response to the first dose and more severe attention deficits prior to treatment. A poorer response was associated with, among other things, higher levels of experienced stress, oppositional defiant disorder or conduct disorder, lower intelligence, and multiple comorbid disorders in preschool age. Many of these findings come from small studies and are sometimes contradictory. It is unclear whether people with ADHD-I (without hyperactivity) respond less well. To date, no EEG measure has met the criteria for a biomarker. Genetic variants, such as those of the alpha-2A receptor (ADRA2A) or the norepinephrine transporter, have shown only inconsistent associations.

The identified characteristics describe probabilities within groups, not definitive predictions for individuals. In practice, therefore, a response to MPH can only be determined through careful trial and error.

1. Response (Responding / Nonresponding)¶

“Response” refers to whether a positive effect on ADHD symptoms can be observed. People with ADHD who do not respond adequately to a medication are called nonresponders.
“Nonresponsive” does not mean that there is no effect, but simply that the effect falls short of the level of symptom improvement defined in the respective study.

There is no uniform definition of response. Of 167 RCTs on ADHD medications, 88 defined a response as a reduction in core symptoms, most commonly as a reduction in the ADHD-RS score by at least 30%, while others specified reductions of at least 25%, 40%, or 50%. 79 RCTs did not specify a threshold. (Systematic review, k = 167 RCTs, full text not available to us, E 1a.)¹

(E 1a): Part of the observed response was due to placebo effects, with:

• A 23.1% reduction in symptoms (a decrease of 8.9 points on the clinician-rated 18-item DSM scale) compared to placebo in an RCT of ADHD medications. The placebo response increased by 63% from 2001 to 2020 and was greater in the U.S. than in other regions. Metaregression (R² = 0.0012) and MetaForest (R² = 0.038) did not reliably predict it (meta-analysis, k = 94 RCTs, N = 6,614 in the placebo group, E 1a.)²
• 18% placebo responders (as assessed by teachers), who would have been classified as MPH responders in the absence of a blinded placebo control (double-blind, placebo-controlled study, n = 118, E 2a.)³
• A placebo response of 10.57 points in the parental assessment compared to 3.93 points in the teacher assessment (Conners Global Index, both p < 0.001). In the parental assessment, it depended, among other things, on income, marital status, education, maternal smoking during pregnancy, and prior experience with stimulants; in the teacher assessment, it depended on ethnicity and prior experience with stimulants (RCT, double-blind, crossover, n = 540, 2 weeks, E 1b.)⁴

(E 2b): The response observed depended on the evaluator and the measuring instrument, with:

• Weak correlation between the MPH effects as assessed by parents and teachers (Conners Total Score, r = 0.09, p = 0.03) and no correlation with laboratory measures (CPT, Restricted Academic Situation Scale) (Secondary analysis of an RCT, double-blind, crossover, n = 526, 2 weeks, E 2b.)⁵
• Lack of correlation between computer-assisted CPT with motion tracking and teacher ratings of individual stimulant effects, despite comparable group effects (secondary analysis of an RCT, crossover design, n = 36, 6 weeks, E 2b.)⁶
• an interaction between teacher and child gender in the assessed MPH effect with a small effect size (η² below 0.02), but not in parent- * S (secondary analysis of an RCT, double-blind, crossover, n = 299, 2 weeks, E 2b.)*⁷

1.1. Response to Amphetamine-Based Medications and MPH¶

A review of 6 controlled crossover studies reported a response rate of at least 69% to amphetamine medications and at least 57% to methylphenidate. At least 87% of people with ADHD responded to one of the two types of active ingredients. The trend in favor of amphetamine was not statistically significant across the individual studies. (Review, k = 6 crossover studies, n = 174, E 2a.)⁸ A network meta-analysis of 32 studies reached a similar conclusion (significantly better response rates to lisdexamfetamine than to MPH or atomoxetine). (Network meta-analysis, k = 32 RCTs, manufacturer-funded, author(s) employed by the manufacturer, E 1a.)⁹
For people with ADHD in whom MPH is ineffective, it is therefore recommended to try treatment with amphetamine-based medications.

True nonresponders to both stimulants were rare in controlled trials conducted across a wide dose range. Of 48 boys, 46 (96%) responded to at least one of the two stimulants; only one was discharged without a recommendation for further stimulant treatment. (Double-blind crossover study, n = 48, 9 weeks, Group 1b.)¹⁰ Six of the 29 children responded only to MPH, and six responded only to D-amphetamine. (Double-blind crossover study, n = 29, E 2a.)¹¹

OROS-MPH and sustained-release amphetamine salts were equally effective and well tolerated in 16- to 19-year-old male and female adolescents with ADHD. No interaction was found between gender and medication, including in driving performance and neuropsychological tests. (Double-blind, randomized crossover study, N = 35, manufacturer-funded, E 1b.)¹²

(E 1b): Testing the same children with MPH and dexamfetamine increased the proportion of responders to:

• 98% (47 out of 48 boys with a recommendation to continue stimulant treatment). Both active ingredients were equally effective in the group; for individual children, one was often superior or was the only one to cause side effects. (Double-blind, randomized crossover study, n = 48, E 1b.)¹⁰
• 92% (33 out of 36) of treatment-naive 9- to 14-year-olds, compared with 72% (26 out of 36) each for those receiving MPH or dexamfetamine alone. MPH was more effective in 13 children, dexamfetamine in 13, and both were equally effective in 7. Switching from the weaker to the more effective active ingredient increased the response rate on the ADHD questionnaire by an average of 64%. (crossover RCT, n = 36, 6 weeks, E 1b.)¹³

Approximately 43% of responders responded preferentially only to sustained-release dexmethylphenidate or only to sustained-release mixed amphetamine salts. (Double-blind crossover RCT, N = 65, n = 56, 8 weeks, manufacturer-funded, E 1b.)¹⁴

In 3 RCTs in which OROS-MPH served as the comparator or reference arm in lisdexamfetamine studies, children and adolescents achieved the following: (Post-hoc analysis, k = 6 studies (4 RCTs, 2 open-label studies), N = 1,823, n = 507 with OROS-MPH, author(s) employed by the manufacturer, E 1b.)¹⁵

• a reduction in ADHD-RS-IV of at least 30%, with a CGI-I score of 1 or 2, in 53.8% to 80.4% of patients (lisdexamfetamine: 69.6% to 82.6%)
• a reduction in ADHD-RS-IV scores of at least 50%, with a CGI-I score of 1 or 2, in 45.3% to 67.9% of patients (lisdexamfetamine: 59.8% to 74.8%)

1.2. Response to MPH and Atomoxetine¶

MPH and Atomoxetine:

• Approximately 50% of people with ADHD who do not respond to MPH are expected to respond to atomoxetine, and approximately 75% of people with ADHD who respond to MPH are also expected to respond to atomoxetine. (Narrative review, E 4)¹⁶
• 43% of MPH nonresponders responded to atomoxetine; 42% of atomoxetine nonresponders had previously responded to OROS-MPH (RCT, N = 516, 6 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)¹⁷
• Similar response rates (at least a 40% reduction on the ADHD-RS-IV) with atomoxetine and MPH, regardless of oppositional behavior (difference 0.6%, 95% CI -11.9 to 13.1), inattention (–3.1%, –11.5 to 5.3) and hyperactivity-impulsivity (–4.9%, –14.3 to 4.4) (Meta-analysis, k = 7 RCTs, N = 1,391, manufacturer-funded, author(s) employed by the manufacturer, E 1a.)¹⁸
• a cognitively defined inhibition control subtype (more delta, theta, and beta activity on qEEG, higher resting heart rate, and higher anxiety) responded significantly better to atomoxetine than a sustained attention subtype (10.5 versus 1.5 points on the ADHD-RS-IV, Cohen’s d = 0.71). Both subtypes responded equally to MPH (13.3 vs. 12.08 points, d = 0.10) (secondary analysis of two studies using cluster analysis, N = 448, 6 weeks, E 2b.)¹⁹

1.3. Predicting Response¶

In practice, it has not yet been possible to predict a child’s response to treatment. One study of preschool children found that, in the United States, white children responded better to stimulants (MPH, lisdexamfetamine) than Black children. Older age and the baseline severity of ADHD symptoms did not moderate the efficacy. The authors considered the subgroup findings to be exploratory. (IPD meta-analysis, k = 2 RCTs, N = 250, supplemented by subgroup data from an additional RCT with n = 165; full text not available to us; E 1a.)²¹
Machine learning enabled a prediction accuracy for response to MPH of just under 85% (as of 2015). (Open-label study, n = 83, 8 weeks, E 2b.)²²

Indicators suggesting a response to MPH included:

• Lower ADHD-RS-IV.es scores (naturalistic cohort study, n = 518, E 2b)³⁶
• the absence of comorbidities (ODD, depression, alcohol/cannabis use) (naturalistic cohort study, n = 518, E 2b)³⁶
• less intrusive neuropsychological tests (naturalistic cohort study, n = 518, E 2b)³⁶
• a higher total IQ (naturalistic cohort study, n = 518, E 2b)³⁶
• Low rates of commission errors (impulse control errors, i.e., responding to a signal that should not have been responded to) on the Conners Continuous Performance Test II (CPT-II) (naturalistic cohort study, n = 518, E 2b)³⁶
• Higher levels of hyperactivity-impulsivity and oppositional symptoms prior to treatment (predictor analysis of an RCT, n = 181, 8 weeks, E 2b)³⁷
  • Predictor of good outcomes with MPH monotherapy, guanfacine monotherapy, and MPH/guanfacine combination therapy
• reduced anxiety prior to treatment (predictor analysis of an RCT, n = 181, 8 weeks, E 2b)³⁷
  • Predictor of good outcomes with MPH monotherapy, guanfacine monotherapy, and MPH/guanfacine combination therapy
• Lower event-correlated midfrontal beta power (greater decrease in power) prior to treatment (predictor analysis of an RCT, n = 181, 8 weeks, E 2b.)³⁷
  • EEG activity from cortical sources in the midfrontal and midoccipital regions
  • Greater modulation during encoding predicts good outcomes with dexmethylphenidate monotherapy, while modulation during retrieval predicts good outcomes with guanfacine monotherapy
• Higher event-related beta power in the middle frontal cortex (weaker decline in power) prior to treatment (predictor analysis of an RCT, n = 181, 8 weeks, E 2b.)³⁷
  • EEG activity from cortical sources in the midfrontal and midoccipital regions
  • Predictor of good outcomes with dexmethylphenidate/guanfacine combination therapy

1.4. Subtypes and Probability of Nonresponse¶

(E 2a): Most older sources report that approximately 90% of people with the ADHD-HI subtype (with hyperactivity) and the combined subtype respond positively to methylphenidate, with more than two-thirds of them responding to moderate to high doses. (Placebo-controlled crossover study, n = 40, E 2a.)³⁹ * (Narrative review, E 4.)⁴⁰ * (Narrative review, E 4.)⁴¹ A retrospective chart review found clinical improvement with stimulants (CGI, after titration after approximately 1 month) in 64% of children with the combined type and 50% of children with ADHD-I. (Retrospective chart review, n = 276, E 3.)⁴²
More recent sources report a response rate of up to 75% for MPH, (full text not available to us, E 4)⁴³ , which seems more accurate to us.

People with the ADHD-I subtype are reportedly more likely to be MPH nonresponders, (narrative review, E 4)⁴⁴ with nonresponder rates of 24% (placebo-controlled crossover study, n = 40, E 2a)³⁹ cited. People with ADHD-I were more likely to respond best to a low dose of MPH (35%), while people with ADHD-HI or mixed-type ADHD predominantly (71%) required moderate to high doses. (Placebo-controlled crossover study, n = 40, E 2a.)³⁹
According to a small study, children with a higher cortisol stress response—which corresponds to the ADHD-I subtype—tended to benefit more from higher doses of MPH than children with a blunted cortisol stress response (which corresponds to ADHD-HI). However, the stress test was not based on the TSST but on a venipuncture, which makes it less easy to clearly detect the cortisol stress response. (Master’s thesis, placebo-controlled, double-blind, crossover study, 4 weeks, full text not available to us, E 2a)⁴⁵

According to parental reports, high cortisol levels upon waking were associated with a lack of response to MPH in children. (Master’s thesis, placebo-controlled, double-blind, crossover study, 4 weeks, full text not available to us, E 2a.)⁴⁵

SCT symptoms (according to current understanding, SCT is not a subtype of ADHD, but rather a comorbidity that occurs with equal frequency in both ADHD-HI and ADHD-I) predicted MPH nonresponsiveness in an RCT. Elevated SCT “Sluggish/Sleepy” factor scores were associated with being an MPH non-responder or placebo responder rather than an MPH responder, and with a weaker dose-response relationship between MPH and inattention. Neither SCT “Daydreamy” symptoms nor ADHD subtype (ADHD-I or mixed type) were associated with the MPH response rate. (Randomized double-blind crossover study, n = 171, 4 weeks, E 1b.)⁴⁶

According to a systematic review, children and adolescents with ADHD and intellectual disabilities responded less well to MPH. The response rate was approximately 40 to 50 percent, compared with approximately 70 to 80 percent among children without intellectual disabilities. (Systematic review, k = 13 RCTs, n = 315, E 1a.)⁴⁷ In contrast, a meta-analysis found that MPH was effective (Hedges’ g = 0.88) in children with ADHD and borderline intelligence or intellectual deficits. (Meta-analysis, k = 8, N = 423, E 1a.)⁴⁸

1.5. (Non-)Responders and EEG Subtypes¶

Stimulant responders had higher EEG theta power than nonresponders. (Prospective study, N = 188, n = 98, at least 4 weeks, E 2b.)⁵⁸
According to our understanding, low theta values correspond to the overactive beta (EEG) subtype. For the BETA subtype (overactive type, accounting for approximately 7% of children with ADHD in an EEG cluster study by the authors), another source reported—based on the authors’ experience—that MPH often elicits adverse reactions, ranging from negative responses to counterproductive effects such as emotional blockage and increased anxiety. (Textbook, E 4.)⁵⁹
The beta subtype manifests externally as the classic ADHD-HI subtype (hyperactive/impulsive). Most people with ADHD-HI have too little theta and too much beta. For more information, visit ⇒ ADHD Subtypes According to EEG.

However, the (few) people with ADHD of the BETA subtype whom we know report that MPH has been extremely helpful. (ADxS experience)

A small study found that lower EEG stability at rest was a predictor of an MPH response. (pilot study, n = 28, E 2b)⁶⁰

A confirmatory multicenter follow-up study did not confirm this in adults. Treatment success (a CAARS reduction of at least 30%) with sustained-release MPH was achieved by 23% of people with ADHD (46% of the sample) and 35% of those with stable arousal regulation (difference of 12 percentage points, 95% CI -5 to 29, p = 0.17), which tends to contradict the hypothesis. (Open-label, single-arm, multicenter study, N = 121, n = 112, 8 weeks, manufacturer-funded, Phase 2b.)⁶¹
In children, more unstable EEG vigilance (less time in stage A1, more stage transitions) was associated with poorer CPT performance before and, to a certain extent, better CPT performance after at least 4 weeks of stimulant treatment (not significant). (Pilot study, N = 98, n = 49, at least 4 weeks, E 2b.)⁶²

A low alpha-peak frequency was associated with a lack of response to methylphenidate in male adolescents. (Open-label prospective multicenter study, N = 494, n = 336, 6 weeks, Phase 2b)⁶⁵

To date, EEG measures, including P3, have not met the criteria for a biomarker of response to MPH. (Systematic review, k = 44, E 2b.)⁶⁶ A stimulant-normalized P300 amplitude was associated with behavioral improvement; early sensory ERP components generally did not change. (Systematic review, k = 43, E 2b.)⁶⁷

Among adults with ADHD, people with and without emotional dysregulation did not differ either in their response to 4 weeks of MPH (responders: 32.1% vs. 27.1%, p = 0.555) or in EEG arousal regulation during resting-state EEG. Comorbid depressive symptoms also did not significantly alter the response (responders: 22.2% vs. 41.4% without depressive symptoms, p = 0.125). (Secondary analysis of a predictive pharmacoeEG study, n = 115, 4 weeks, E 2b.)⁸⁰

Children with ADHD of the combined type who responded well to MPH showed a pattern of cortical underactivation on resting-state EEG, whereas those who responded well to dexamfetamine showed a pattern suggestive of delayed maturation. The authors interpreted this as evidence of two distinct central nervous system dysfunctions and as indicating the need to test the medication before prescribing it. (Case-control study, 20 good and 20 poor responders per active ingredient, 20 controls, N = 100, E 3.)⁶⁸

1.6. (Non-)Responders and the D1R-to-D2R Ratio¶

A PET study involving 37 healthy participants found: (Single-blind, placebo-controlled crossover study, n = 37, Phase 2b.)⁸¹
MPH was more effective in people with relatively more D2R in the dorsomedial caudate; people with relatively more D1R benefited only slightly.

1.7. (Non-)Responders and MPH Dosage¶

Some observers speculate that nonresponders may be cases of underdosing—that is, that the required dosage was not achieved and a lack of response is merely assumed. (Narrative Review, E 4)⁸²
In our experience, a dosage that is too low can cause what appears to be a lack of response. Nevertheless, there are genuine nonresponders for whom even significantly increased doses do not produce satisfactory results.
In addition, different nonresponder rates have been reported among children and adults.
We suspect that a more precise classification of ADHD subtypes will eventually provide some answers here.

Children whose attention in class did not improve with low doses of MPH were 65 to 74 percent likely to show improvement after a dose increase. In contrast, for academic performance and behavior, a lack of response to low doses predicted a lack of response to higher doses as well. A significant improvement or normalization was observed with at least one dose (5, 10, 15, or 20 mg) for: (double-blind, placebo-controlled crossover study, n = 76, Phase 2b.)⁸³

• Behavior in the teacher’s evaluation: 94%
• Attention: 76%
• Academic performance: 53%

Body weight did not predict the dose-response curve, the optimal dose, the gain achieved at the optimal dose, or responder status. (Double-blind, placebo-controlled crossover study, n = 76, Phase 2b.)⁸⁴

1.8. Does the Season Affect MPH Dosage?¶

A study found a seasonal pattern of inattention among people with ADHD who were treated with low-dose MPH. During the time of year when light levels increase (as days grow longer), people on low doses showed relatively poorer attention. It was not the absolute amount of light, but rather its relative change, that was relevant. High doses of MPH led to higher levels of attention that fluctuated less throughout the year. A greater reduction in sunlight intensity was associated with a better response to treatment. These results were also evident in omission errors on a CPT. (Open-label multicenter study, N = 336, n = 268, 6 weeks, Phase 2b)⁸⁵
The authors interpreted this to mean that, when treatment begins as the days grow shorter, a low dose of MPH may be sufficient.
A link to the circadian rhythm is suspected. The authors hypothesize that in some people with ADHD (who require less MPH?), there may be impaired function of the light-sensitive retinal cells in the ADHD subgroups, affecting the melatonin- and dopamine-producing cells in the retina. They raise the question of whether a combination of MPH and modulated light therapy could improve treatment response, as has already been reported for fluoxetine in non-seasonal depression. (RCT, N = 122, 8 weeks, E 1b)⁸⁶

1.9. Indicators of a Good Response to MPH¶

1.9.1. Clinical and Demographic Characteristics¶

In preschool-aged children with ADHD, low levels of externalizing or internalizing symptoms correlated with a high probability of responding to stimulants. When externalizing or internalizing symptom severity was high, the response rate to stimulants approached that of alpha-2 agonists (response rate calculated as 100% minus the proportion of nonresponders): (Retrospective chart review, N = 309, n = 195, E 3.)⁸⁷

Responder	Symptom severity:	mild	moderate	severe
Stimulants	Externalizing	96.4%	74.3%	66.6%
Alpha-2 agonists	Externalizing	40%	50%	67%
Stimulants	Internalizing	80.6%	77.5%	50%
Alpha-2 agonists	Internalizing	57.7%	70%	57.7%

People with ADHD for whom medication was ineffective (nonresponders) reported higher levels of perceived stress on the Perceived Stress Scale (PSS) than people with ADHD for whom it was effective (responders). (Cross-sectional study, N = 202, n = 76 with ADHD, E 3.)⁸⁸

(E 1b): A better response to MPH was predicted by:

• high levels of hyperactivity at school and younger age (normalization of hyperactivity in at least one setting), which together, however, correctly classified only 71% of the boys (RCT, double-blind, crossover, n = 36, E 1b.)²⁴
• more severe executive function deficits (reaction time variability β = 0.670, p = 0.042) and more severe ADHD symptoms in adults taking OROS-MPH (RCT, crossover, n = 22, 6 weeks, E 1b.)⁸⁹
• A low dose of MPH prior to switching to sustained-release MPH is associated with a higher probability of belonging to one of the two (out of a total of four) outcome groups showing marked improvement (Observational study, N = 822, 3 months, manufacturer-funded, E 2b.)⁹⁰
• Clinical improvement following a single dose of MPH, which predicted symptom improvement after 4 weeks of MPH treatment. Of 63 single-dose RCTs, only one secondary analysis (n = 46) examined this association (Evidence for the statement: secondary analysis of an RCT) (Systematic review, k = 63 RCTs, full text not available to us, E 1a.)⁹¹

(E 2b): Clinical and demographic characteristics prior to treatment predicted a better response to MPH in

• more severe ADHD symptoms in:
  • Adults on immediate release MPH as the sole predictor (b = 0.770), independent of comorbidities (Naturalistic study, n = 250, E 2b.)⁹²
  • In adults, OROS-MPH (CAARS) was the strongest predictor of (post hoc analysis of an RCT, N = 401, 12 weeks, author(s) employed by the manufacturer, E 2b.)⁹³
  • Adults taking MPH or atomoxetine, along with comorbid substance use disorder (49.3% responders, d = 0.72) (Naturalistic study, N = 150, n = 75, full text not available to us, E 2b.)⁹⁴
  • Children and adolescents undergoing MPH or neurofeedback as the most relevant predictor (RCT, n = 146, author(s) employed by a neurofeedback manufacturer, E 2b.)⁹⁵
  • Children with intellectual disabilities (IQ 48 to 77) who, according to their parents, exhibit higher levels of impulsivity and activity (double-blind, placebo-controlled study, n = 47, E 2b.)⁹⁶
  • Boys with a higher hyperactivity factor (r = 0.18, trend) (longitudinal study, n = 84, E 2b.)⁹⁷
• older age in:
  • Boys (r = 0.36) (longitudinal study, n = 84, E 2b.)⁹⁷
  • Children and adolescents following a single dose of MPH for attention and working memory (29.2% and 22.4% of variance explained, respectively) (single-dose study, n = 48, Phase 2b)⁹⁸
• family history of:
  • ADHD in first-degree relatives and antisocial personality disorder in second-degree relatives: good responders (74 good responders, 44 poor responders) (Family study of a double-blind, placebo-controlled crossover RCT, n = 118, 2 weeks, E 2b.)⁹⁹
  • similar responses within families (intraclass correlation: hyperactivity/impulsivity 0.86, total symptoms 0.81, CGI-I 0.68, inattention 0.61) among 19 sibling or parent-child pairs (open-label study, n = 38, 4 weeks, E 2b.)¹⁰⁰
• higher IQ and greater anxiety in teacher ratings (together explaining 18% of the variance; not a predictor in parent ratings) (RCT comparing MPH to MPH plus behavioral therapy, n = 50, 10 weeks, E 2b.)¹⁰¹
• more perinatal complications (r = 0.25) (longitudinal study, n = 84, E 2b.)⁹⁷
• male gender in the case of:
  • Children with intellectual disabilities, who are also white and have a higher socioeconomic status (double-blind, placebo-controlled study, n = 47, E 2b.)⁹⁶
  • Adults for individual endpoints, as well as those with lower educational attainment (post-hoc analysis of an RCT, N = 401, 12 weeks, author(s) employed by the manufacturer, E 2b.)⁹³
• higher baseline weight and prior atomoxetine treatment for remission at 12 months (Prospective observational study, N = 455, n = 221 receiving MPH, 12 months, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)¹⁰²
• Sleep characteristics in:
  • Shorter sleep duration prior to treatment, as reported by parents, regardless of baseline severity (stimulants) (Prospective study, n = 50, full text not available to us, E 2b.)¹⁰³
  • more severe sleep disturbances with greater stabilization of reaction time variability following a single dose of MPH (Retrospective single-dose study, n = 43, E 3.)¹⁰⁴
• high IQ, marked inattention at school, younger age, lower baseline severity, and low levels of anxiety at home were associated with improvement both at home and at school (81% correctly classified) (Double-blind, placebo-controlled study, N = 52, n = 46, 4 weeks, E 2b.)¹⁰⁵

Meeting the age criterion (onset of symptoms more than 7 years ago) was not associated with a better response to MPH. Adults with late-onset disease actually responded better (F = 5.76, p = 0.018), while there was no difference among children and adolescents (F = 0.865, p = 0.354). (Naturalistic study, N = 291, 1 month, E 2b.)¹⁰⁶

(E 2b): A better response to MPH was associated with:

• Comorbid ODD or disorder of conduct without adjustment for other comorbidities (more frequent good response, p = 0.01; no longer significant after adjusting for anxiety, depression, and income, OR 1.66, 95% CI 0.89 to 3.11) (Double-blind, placebo-controlled crossover study, n = 267, 2 weeks, E 2b.)¹⁰⁷
• Low family income (household income below $20,000, OR 0.49, 95% CI 0.26 to 0.91, independent of age and sex) (Double-blind, placebo-controlled crossover study, n = 267, 2 weeks, E 2b.)¹⁰⁷
• older age:
  • greater percentage reduction in symptoms (β = -0.45, SE 0.08, p < 0.001) (Pooled analysis and metaregression, k = 9, N = 782, E 2b.)¹⁰⁸
  • Higher probability of response across all medications (OR 1.053, 95% CI 1.017 to 1.091); not significant in the MPH monotherapy group (Retrospective study, N = 1,314, 1,590 treatment episodes, E 3.)¹⁰⁹
• more severe initial condition (for contrary findings, see ⇒ 5.7):
  • greater percentage reduction in symptoms (β = -0.41, SE 0.06, p < 0.001) (pooled analysis and metaregression, k = 9, N = 782, E 2b.)¹⁰⁸
  • a 25% or greater improvement in parental ratings (total CPRS, OR 1.07, 95% CI 1.04 to 1.1) (Naturalistic study, n = 345, E 2b.)¹¹⁰
• In medication-naive adults, greater executive function impairment (BRIEF-GEC, OR 1.13 per T-point, 95% CI 1.02 to 1.25) and better quality of life (Q-LES-Q, OR 1.23, 95% CI 1.05 to 1.45), with a combined AUC of 0.81 (MPH or amphetamine medications, 50% responder rate) (Prospective naturalistic study, n = 36, average 116 days, E 2b.)¹¹¹
• Greater gray matter volume in the head of the caudate nucleus bilaterally and in the right nucleus accumbens (16 good responders versus 11 poor responders, medication-naive children). The volume correlated with improvement on the CPRS and the CPT (MRI study, n = 27, 1 month, E 2b.)¹¹²

1.9.2. Neuropsychological Characteristics¶

(E 2b): Pre-treatment neuropsychological characteristics predicted response to MPH in:

• greater variability and skewness, as well as lower complexity, in reaction time series (CPT II) among responders, which normalized only in responders receiving MPH (adults, 63% responders according to CGI-I) (Open-label prospective study, N = 123, 6 weeks, Phase 2b.)¹¹³
• more severe attention deficits (encoding, memory retrieval, decision-making, focused and sustained attention, vigilance) in responders than in nonresponders. Medical history, IQ, and neurological findings did not distinguish between the groups. (Case-control study with an RCT crossover design for responders, N = 85, n = 58, 4 weeks per phase, E 2b.)¹¹⁴
• higher commission error rates on the CPT, which correlated with improvement in ODD symptoms in ADHD with ODD and with improvement in teacher ratings in ADHD without ODD (Prospective study, n = 53, 12 weeks, E 2b.)¹¹⁵
• higher self-reported BRIEF-A score for working memory (adults, MPH or amphetamine, r = 0.42) (prospective study, n = 36, approximately 4 months, E 2b.)¹¹⁶
• Baseline scores for attention and working memory, as well as ADHD severity, predicted improvement following a single dose. Emotional and behavioral symptoms did not predict improvement, with the exception of symptoms of social behavior disorders. (Single-dose study, n = 48, E 2b.)⁹⁸
• Age and performance on a memory distraction task and the Graduated Holes Task (together accounting for approximately 50% of the variance in clinical response). Changes in test scores were barely associated with clinical improvement. (Clinical study, n = 26, E 2b.)¹¹⁷

Neurocognitive indices (CPT, BRIEF) had only limited prognostic value in children and adolescents for response to MPH or neurofeedback and were more suitable as markers of progress during MPH treatment (commission errors, reaction time variability, BRIEF total score). (RCT, n = 146, author(s) employed by a neurofeedback manufacturer, E 2b.)⁹⁵

1.9.3. Reaction to the first dose of MPH¶

A greater increase in systolic blood pressure following acute MPH administration correlated with a greater improvement in attentional performance on the CPT. (Exploratory analysis, n = 513, E 2b.)¹¹⁸

(E 2b): The response to an initial dose of MPH—or the early response—predicted the subsequent response in:

• Improvement in hyperactivity/impulsivity (BAARS-IV) and QbTest scores following 20 mg of MPH compared with placebo, with improvement observed after 2 months (adults, p < 0.001). Multivariate models incorporating single-dose response and baseline characteristics yielded correlations between predicted and actual outcomes of up to r = 0.69. (Placebo-controlled single-dose study, n = 60, 2 months, manufacturer-funded, Phase 2b.)¹¹⁹
• Response to a single 10-mg dose of MPH, resulting in improvement both at home and at school after 4 weeks (positive predictive value 78%, negative predictive value 68%, 70% correctly classified) (Double-blind, placebo-controlled trial, N = 52, n = 46, 4 weeks, Phase 2b.)¹⁰⁵
• a greater increase in blood pressure following the first dose of MPH, with a greater reduction in symptoms after 6 months (total β = 0.233; hyperactivity/impulsivity β = 0.225; inattention β = 0.202) (Retrospective chart review, N = 171, 6 months, full text not available to us, E 3.)¹²⁰
• Decreased functional connectivity (SSVEP coherence) 90 minutes after the first MPH dose in the frontal-prefrontal region, associated with an improvement in hyperactivity, and in the occipital-parietal region, associated with an improvement in inattention, after 3 months (stimulant-naive boys) (Prospective study, n = 40, 3 months, Phase 2b)¹²¹
• Higher scores for “wanting” (incentive salience) and “liking” (hedonic experience) after a single dose among responders (24 of 29) compared with nonresponders and controls (MPH or lisdexamfetamine). “Wanting” correlated with changes in connectivity in the ventral striatum, including the nucleus accumbens. (case-control study using fMRI, N = 54, n = 29; full text not available to us, E 3.)¹²²
• Response at Week 3 (at least a 20% reduction in symptoms) and Week 12 (at least a 40% reduction) was associated with fewer symptoms after 3 years (ADHD-RS 24.1 vs. 29.6 and 26.0 vs. 34.2, respectively), regardless of other predictors; however, in the adjusted analysis, this was not associated with the functional level (Clinical cohort study, n = 148, 3 years, E 2b.)¹²³

Higher plasma MPH levels and the absence of side effects following the test dose predicted an improvement in concentration after acute MPH administration in adults with ADHD; plasma levels also predicted an improvement in tension. Patients who showed improvement in concentration, hyperactivity, and impulsivity had significantly higher plasma levels than those who did not show improvement (p = 0.001 to 0.004). (Prospective challenge study, n = 71, single dose, Phase 2b.)¹²⁴

1.9.4. Neurobiological Characteristics¶

Elevated iron levels in the putamen and caudate were correlated with better MPH response in ADHD. Elevated iron levels in the putamen were correlated—not only in ADHD—with impaired inhibition. (Imaging study with randomized, placebo-controlled MPH crossover administration, N = 65, n = 36, E 2b)¹²⁵

1.9.5. Genetic Traits¶

1.10. Indicators of Poor Response to MPH¶

1.10.1. Stress and Childhood Trauma¶

People with ADHD for whom medication was ineffective (nonresponders) reported higher levels of perceived stress on the Perceived Stress Scale (PSS) than people with ADHD for whom it was effective (responders). (Cross-sectional study, N = 202, n = 76 with ADHD, E 3.)⁸⁸

In unaffected individuals, the number of traumatic childhood events correlated with the level of currently experienced stress as well as with a stronger dopamine response in the ventral striatum to amphetamine. (PET correlation study, n = 28, E 3)¹⁴⁴
This could be an indication that increased childhood trauma is associated with an increased striatal dopamine response to stimulants, meaning that a significantly lower dose of stimulants would be more appropriate for these individuals. We can immediately think of people with ADHD for whom this is true. (ADxS experience)

1.10.2. Comorbidities, Clinical and Neurobiological Characteristics¶

Children with mixed-type ADHD who had never been treated with stimulants and who had comorbid behavioral disorders showed less marked improvement on working memory and attention tests while taking OROS-MPH than children without comorbid behavioral disorders. (Pilot study with a control group, N = 23, n = 12, 1 month, E 2b.)¹⁴⁵

(E 2b): Comorbid anxiety disorders or internalizing symptoms were associated with

• poorer response to MPH in:
  • Anxiety disorder without other comorbidities (less frequent good response, OR 0.38, 95% CI 0.16 to 0.89, independent of age, sex, and income, 0.5 mg/kg/day) (Double-blind, placebo-controlled crossover study, n = 267, 2 weeks, E 2b.)¹⁰⁷
  • Anxiety disorder (less frequent improvement of 25% or more as assessed by teachers, CTRS, OR 0.32, 95% CI 0.11 to 0.99; poorest response of all subgroups in the OROS-MPH) (Naturalistic study, n = 223, 1 month, E 2b.)¹⁴⁶
  • pronounced internalizing symptoms (positive response in teacher ratings at doses below 15 mg in 25%, no internalizing symptoms at doses above 60%, and a deterioration in classroom behavior in 25% compared to 9.1% and 0%) (Double-blind, placebo-controlled study with 3 doses, n = 40, E 2b.)¹⁴⁷
  • Anxiety disorder affecting cognitive performance (less improvement on the WISC Digit-Symbol Test and in the Symbol Search task; behavioral response remained the same) (pilot study, n = 18, 4 to 6 weeks, E 2b.)¹⁴⁸
  • Anxiety disorder affecting working memory (improvement in auditory-verbal manipulation and visuospatial memory observed only in participants without an anxiety disorder; visuospatial manipulation improved in both groups, with 32% of participants having an anxiety disorder) (Randomized, double-blind, placebo-controlled crossover study with 3 doses, n = 130, Phase 2b.)¹⁴⁹
• no difference in response in the following cases:
  • Anxiety disorder (50% or greater improvement on the SNAP-IV after 1 month in 32.8% of those with anxiety disorder compared with 27.6% of those without, p = 0.47, Effect size of the group difference 0.27) (Naturalistic study, n = 280, 1 month, E 2b.)¹⁵⁰
  • Anxiety disorder (no difference in behavior or side effects after titration or after 4 months; children with anxiety disorder reached a lower dose at the end of titration) (Randomized, placebo-controlled trial, n = 91, 4 months, Phase 2b.)¹⁵¹

(E 2b): Emotional dysregulation was associated with

• higher ADHD-RS scores after 4 weeks of MPH treatment in children and adolescents (CBCL dysregulation profile, total B = 0.13, p = 0.04; hyperactive-impulsive B = 0.10, p = 0.04; not for inattention; callous-unemotional traits had no effect) (Open-label study, n = 43, 4 weeks, E 2b.)¹⁵²
• No difference in the response rate among adults (32.1% vs. 27.1%, p = 0.555; among those with comorbid depressive symptoms, 22.2% vs. 41.4%, p = 0.125) (Secondary analysis of a predictive pharmacoeEG study, n = 115, 4 weeks, E 2b.)⁸⁰

(E 2b): Other comorbidities were associated with a poorer response to MPH in the following cases:

• ODD (Oppositional Defiant Disorder) or social behavior disorder:
  • smaller percentage reduction in symptoms for ODD (β = 9.58, SE 2.38, p < 0.001) (Pooled analysis and metaregression, k = 9, N = 782, E 2b.)¹⁰⁸
  • A 25% or greater reduction in teacher-reported symptoms of ODD/CD was less common (OR 0.47, 95% CI 0.29 to 0.78) (Naturalistic study, n = 345, E 2b.)¹¹⁰
  • Poorer response in cases of comorbid ODD (SNAP-IV, p = 0.03) (Naturalistic longitudinal study, n = 125, 6 months, E 2b.)¹⁵³
  • Lower probability of response with MPH monotherapy for disorder (OR 0.535, 95% CI 0.294 to 0.977) (Retrospective study, N = 1,314, 1,590 treatment episodes, E 3.)¹⁰⁹
  • Conversely, a higher rate of good response was observed in ODD or CD (p = 0.01; not significant after adjustment); see ⇒ 5.6 (double-blind, placebo-controlled crossover study, n = 267, 2 weeks, Phase 2b)¹⁰⁷
• borderline or below-average intelligence:
  • Excellent response rate: 10% for participants with below-average IQ, 48% for those with average or above-average IQ (only in the subgroup with parental depression and high baseline severity, in the medication and combination arms of the MTA) (Secondary analysis of an RCT, N = 579, n = 41 in this subgroup, 14 months, E 2b.)¹⁵⁴
  • Borderline intelligence among patients on MPH monotherapy: OR 0.404 (95% CI 0.237 to 0.690) (Retrospective study, N = 1,314, 1,590 treatment episodes, E 3.)¹⁰⁹
• Autism Spectrum Disorder:
  • Lower probability of response with MPH monotherapy (OR 0.405, 95% CI 0.211 to 0.779) (Retrospective study, N = 1,314, 1,590 treatment episodes, E 3.)¹⁰⁹
  • Conversely, there was no difference in efficacy or in the number of clinically relevant adverse effects between patients with high and low ASA symptoms (medication after 3 months was predominantly MPH, 75% and 77%, respectively; not analyzed separately) (Prospective cohort study, n = 323, 3 months, Phase 2b.)¹⁵⁵
• Other comorbidities associated with MPH monotherapy: (Retrospective study, N = 1,314, 1,590 treatment episodes, E 3.)¹⁰⁹
  • Enuresis OR 0.239 (95% CI 0.107 to 0.535)
  • Adjustment disorder OR 0.242 (95% CI 0.082 to 0.719)
  • Communication disorders OR 0.221 (95% CI 0.071 to 0.682)
• Learning disabilities (less frequent improvement of 25% or more as assessed by teachers, OR 0.44, 95% CI 0.26 to 0.77) (Naturalistic study, n = 345, E 2b.)¹¹⁰
• 3 or more comorbidities in preschool children (d = -0.37 for 7.5 mg compared with placebo; for 0 to 2 comorbidities, d = 0.56 to 1.00), see ⇒ 2.13 (moderator analysis of an RCT (PATS), N = 165, 5 weeks, E 2b.)¹⁵⁶
• Cocaine dependence in adults (symptom reduction: 34% vs. 56%; responders: 38% vs. 75%; not significant). MPH bound to fewer striatal DAT receptors in cocaine dependence, but DAT binding did not correlate with symptom improvement; see ⇒ 2.1.1.2 (open-label SPECT study, n = 24, 2 weeks, E 2b.)¹⁵⁷

(E 2b): Parental and psychosocial factors were associated with a poorer response to MPH in:

• Parental depression (excellent response rate of 45% for BDI scores of 9 or higher, 69% for BDI 8 or lower, OR 0.37, 95% CI 0.22 to 0.62; medication and combination arms of the MTA; no effect in the behavioral therapy and control arms) (Secondary analysis of an RCT, N = 579, 14 months, E 2b.)¹⁵⁴
• maternal ADHD symptoms (p < 0.001) (naturalistic longitudinal study, n = 125, 6 months, E 2b.)¹⁵³
• maternal antisocial symptoms (25% or greater improvement as reported by parents, OR 0.83, 95% CI 0.75 to 0.92) (Naturalistic study, n = 223, 1 month, E 2b.)¹⁴⁶
• maternal antisocial symptoms (25% or greater improvement as assessed by teachers, OR 0.9, 95% CI 0.82 to 0.99) (naturalistic study, n = 223, 1 month, E 2b.)¹⁴⁶
• maternal symptoms of anxiety and depression (improvement of 25% or more as assessed by parents, OR 0.95, 95% CI 0.9 to 0.99) (Naturalistic study, n = 223, 1 month, E 2b.)¹⁴⁶
• unintended pregnancy (p = 0.02, as the only one of several psychosocial stressors) (naturalistic longitudinal study, n = 125, 6 months, E 2b.)¹⁵³

(E 2b): Baseline severity and subtype were associated with a poorer response to MPH in:

• more severe initial presentation (for contrary findings, see ⇒ 5.6):
  • Excellent response rate of 41% compared to 73% for participants with a baseline SNAP-IV score above 2.63 (children of parents with a BDI score of 8 or lower, medication and combination arm of the MTA, OR 0.26) (Secondary analysis of an RCT, N = 579, n = 193 in this subgroup, 14 months, E 2b.)¹⁵⁴
  • severe versus moderate severity while on MPH monotherapy (OR 0.237, 95% CI 0.102 to 0.548) (Retrospective study, N = 1,314, 1,590 treatment episodes, E 3.)¹⁰⁹
  • A higher total SNAP-IV score as an independent risk factor for non- (Prospective study, n = 150, 3 months, Phase 2b.)¹⁵⁸
• combined subtype:
  • poorer response (p < 0.001) (naturalistic longitudinal study, n = 125, 6 months, phase 2b)¹⁵³
  • Independent risk factor for non- (Prospective study, n = 150, 3 months, Phase 2b)¹⁵⁸
• Contrary to the predominantly inattentive subtype (less commonly, at least minimal improvement on the CGI; OR 0.6, 95% CI 0.4 to 0.98, OROS-MPH) (Naturalistic study, n = 223, 1 month, E 2b.)¹⁴⁶

Greater variability in reaction time prior to treatment characterized nonresponders to OROS-MPH (Mann-Whitney U = 577, p < 0.01). It predicted response (Nagelkerke R² = 0.136) and correctly classified 94.9% of responders but only 17.2% of nonresponders. 67% (59 out of 88) responded. (Prospective, open-label, multicenter study, N = 144, n = 88, 12 weeks, manufacturer-funded, Phase 2b.)¹⁵⁹

Among treatment-naive adults, higher scores on the Adult Self-Report (ASR) for thinking problems, withdrawal, internalizing problems, and intrusive thoughts were associated with a reduced effect of stimulants. 71% of people with ADHD on MPH, but 36% on amphetamine medications, were responders at the end of the study (p = 0.04). Nonresponders switched medications more frequently (56% versus 11%). (Naturalistic prospective study, n = 36, average 116 days, Phase 2b.)¹¹¹

Mood and anxiety-related side effects (irritability, tearfulness, anxiety) associated with MPH and placebo were linked to a smaller improvement in parental ratings, but not in teacher ratings. Physical side effects (insomnia, loss of appetite, headaches) did not correlate with treatment response. The authors interpreted this association as an observer effect. (Double-blind, placebo-controlled crossover study, n = 157, 1 week each, 0.5 mg/kg/day, Phase 2b.)¹⁶⁰

Children who did not respond to MPH (SNAP-IV after 3 months, 34 out of 150) had lower pre-treatment serum levels of 25(OH) vitamin D, cortisol, S100β, and BDNF, as well as lower urinary catecholamines. Independent risk factors included combined subtype, a higher SNAP-IV score, lower vitamin D levels, and lower dopamine levels. A random forest model achieved an AUC of 0.883 (95% CI 0.811 to 0.956) and an accuracy of 86.67% in the test dataset. (Prospective study, n = 150, 3 months, E 2b.)¹⁵⁸ Ferritin levels and iron deficiency (ferritin below 12 ng/mL) did not influence the short-term response. (Naturalistic study, n = 345, E 2b.)¹¹⁰

(E 2b): Nonresponders and poor responders differed from responders in the following ways:

• higher resting blood flow (rCBF, SPECT) in the left and right anterior cingulate, the left claustrum, and the right putamen, as well as lower levels in the right superior parietal lobe prior to treatment (10 nonresponders, 24 responders, discriminant analysis 88.2% accuracy) (SPECT study, n = 34, 8 weeks, E 2b.)¹⁶¹
• Larger volumes of the amygdala on both sides and the right thalamus, as well as larger subregions of the amygdala and hippocampus, prior to treatment (23 nonresponders, 44 responders) (MRI study, N = 92, n = 67 with ADHD, 8 weeks, E 2b.)¹⁶²
• Lower gray matter volume in the head of the caudate nucleus bilaterally and in the right nucleus accumbens prior to treatment (11 poor responders, 16 good responders), see ⇒ 5.6 (MRI study, n = 27, 1 month, E 2b.)¹¹²
• Smaller left dorsal superior longitudinal fasciculus (SLF I) in adults; see ⇒ 5.11 (DTI longitudinal study, N = 80, n = 60 with ADHD, 2 months, manufacturer-funded, E 2b.)¹⁶³
• atypical age-related increase in resting-state connectivity in the cingulo-opercular network (stimulants), see ⇒ 2.10.1 (longitudinal study, N = 252, n = 110 with ADHD, up to 5 measurement time points, E 2b.)¹⁶⁴
• Activation of the prefrontal pole from rest to concentration (SPECT) in people with ADHD who have an adverse reaction to stimulants, deactivation in cases of a good response (left pole sensitivity 0.71, specificity 0.84; right pole 0.69 and 0.86, respectively; authors from a commercial SPECT clinic) (Retrospective chart review, N = 157, E 3.)¹⁶⁵

MPH induced significant right-hemispheric activation in children with ADHD without ASD (fNIRS, Go/No-Go task), whereas in children with ADHD and comorbid ASD, it induced only minimal activation. The MPH-induced activation distinguished between the two groups with a specificity of 86%, a sensitivity of 93%, and an accuracy of 82%. (Randomized, double-blind, placebo-controlled crossover study, n = 32, single dose, Phase 2b.)¹⁶⁶

1.11. Gene Variants and the Effect of MPH¶

1.11.1. ADRA2A gene variants¶

1.11.2. NET gene variants¶

1.12. CES1 Plasma Protein Levels and MPH Dosage¶

Methylphenidate is metabolized by the CES1 liver enzyme.
In 15 healthy adults, a higher CES1 plasma concentration correlated with a reduced d-methylphenidate plasma level (AUC) following a single dose of MPH. The CES1 plasma protein level accounted for approximately 50% of the variability in d-methylphenidate plasma levels. In a simulation involving children, an individualized dosing regimen based on CES1 reduced the variability of d-methylphenidate plasma levels by about 50% compared to a fixed dose. An individualized dosing strategy based on CES1 measurements could potentially facilitate the titration of d-methylphenidate. (Correlation study with PBPK simulation, n = 15, single dose, E 3.)¹⁸⁵

1.13. Response varies from person to person depending on the degree of retardation and the carrier substance¶

People with ADHD report that their response to various MPH medications varies greatly from person to person.
While it is now generally recognized that there are intraindividual (within a single person) and interindividual (compared to other people with ADHD) in terms of tolerance to extended-release MPH formulations is now generally recognized, it is less well known that tolerance and response can also vary greatly within a single individual when it comes to different MPH formulations with immediate release. We have received reports from numerous people with ADHD who consistently perceive very distinct differences in the effects of various immediate-release MPH formulations of the same strength. (ADxS experience)¹⁹¹ * (ADxS experience)*¹⁹²

1.14. Responding to Fractional Anisotropy of the White Matter¶

1.14.1. Microstructure of the white matter¶

A study that classified children with ADHD into two subgroups based on white matter microstructural features (DTI) found no differences in ADHD symptoms; however (MPH response recorded retrospectively from medical records for only 52 children): (Cross-sectional study with cluster analysis, N = 316, n = 227 with ADHD, E 3.)¹⁹³

• Better MPH response when
  • reduced fractional anisotropy of the white matter
  • correlated with
    • reduced processing speed
• Poorer MPH response in
  • higher fractional anisotropy of the white matter
  • correlated with
    • reduced response inhibition
    • reduced sustained attention

1.14.2. Additional imaging predictors¶

2. Additional Genetic Factors Affecting the Efficacy of MPH¶

In addition to CES1, several other genes influence the efficacy of MPH.

(E 2b): Genome-wide and polygenic approaches have so far failed to identify clinically useful predictors of response to MPH or stimulants:

• genome-wide association studies:
  • No genome-wide significant hit (best p = 3 × 10⁻⁶), suggestive of GRM7 rs3792452 (p = 2.6 × 10⁻⁵), MPH patch, children (genome-wide association study in an open-label trial, n = 187, E 2b.)²⁰¹
  • No genome-wide significant hits; genes nominally associated were enriched for ADHD candidate genes; 33 eSNPs were tested in children and adults (Genome-wide association study with replication, N = 362, n = 173 children, n = 189 adults, E 2b.)²⁰²
  • 39% discontinued stimulant use within 1 year, SNP heritability 0.06 (95% CI 0.02 to 0.11), 0.08 in children (95% CI 0.02 to 0.14), 0.14 in adolescents and adults (95% CI 0.02 to 0.27); a genome-wide significant locus (SLC5A12) was found only in children (register-based cohort study, N = 18,362, 1 year, E 2b.)²⁰³
  • 45% discontinued treatment within 2 years; 15% switched to non-stimulant medications; SNP heritabilities not significantly different from zero; one genome-wide significant locus (16q23.3) only for the switch to (registry cohort study, N = 9,133, E 2b.)²⁰⁴
• polygenic scores:
  • None of the PGSs for ADHD, autism, bipolar disorder, educational achievement, depression, neuroticism, and schizophrenia were associated with MPH response; small effects that were consistent across cohorts (Norway, Brazil, Spain) (Meta-analysis, k = 3 cohorts, N = 1,000, E 2b.)²⁰⁵
  • Schizophrenia-PRS (HR 1.07, 95% CI 1.03 to 1.11) and Bipolar-PRS (HR 1.05, 95% CI 1.02 to 1.09) were associated with more frequent discontinuation; ADHD and autism PRS showed no association (register-based cohort study, N = 9,133, E 2b.)²⁰⁴
  • 10 of 36 PGSs were associated with discontinuation; PGSs with higher psychiatric risk were associated with more frequent discontinuation (register-based cohort study, N = 18,362, 1 year, E 2b.)²⁰³
• Reviews and guidelines:
  • No single variant and no available pharmacogenomic test with proven clinical benefit for drug selection in children (Narrative review, studies from 2009 to 2019, E 4.)²⁰⁶
  • In adults, findings are almost exclusively negative; the only positive finding is for DAT1; pharmacogenetic testing is far from routine (Systematic review, k = 5, E 2b.)²⁰⁷
  • No gene-drug interaction between CYP2D6 or COMT and methylphenidate (Dutch pharmacogenetics guideline) (Guideline, E 4.)²⁰⁸
  • Study design (open-label versus randomized controlled) was the only one of the five study factors to explain the heterogeneity of the results (p = 0.001), study location and ethnicity did not * Ly (pooled analysis and metaregression, k = 9, N = 782, E 2b.)*¹⁰⁸
• Candidate genes in adults: no association between SLC6A4, HTR1B, TPH2, DBH, DRD4, COMT, and SNAP25 and response to MPH (Naturalistic study, n = 164, E 2b.)²⁰⁹

Response to MPH correlated strongly among siblings with ADHD (intraclass correlation r = 0.563, p = 0.001), suggesting a familial clustering of response. (Sibling study, n = 82 from 54 families, E 3.)²¹⁰

2.1. Genes Involved in Neurotransmitter Synthesis and Degradation Influence the Effects of MPH¶

2.2. Neurotransmitter reuptake transporter genes influence the effects of MPH¶

2.2.1. Norepinephrine transporter gene (SLC6A2)¶

2.2.2. Dopamine transporter gene (SLC6A3, DAT1)¶

2.2.3. Serotonin transporter gene (SLC6A4)¶

2.3. Receptor Genes Influence the Effects of MPH¶

2.3.1. Dopamine receptor genes¶

2.3.2. Adrenoceptor, glucocorticoid receptor, serotonin receptor, and acetylcholine receptor genes¶

2.4. Genes Involved in Neurotransmitter Release Influence the Effects of MPH¶

2.5. Genes Involved in Neural Plasticity and Synaptic Effectors Influence the Effects of MPH¶

¶

3. Therapeutic Reference Range, Pharmacokinetics¶

3.1. Therapeutic Reference Range¶

The therapeutic reference range (Cmax ranges for therapeutically effective doses) was specified as follows:

• Methylphenidate: (Summary of a consensus guideline, E 4)²⁸⁶

  • Children and adolescents:
    • 6 to 26 ng/mL, 2 hours after taking 20 mg of the IR formulation or 4 to 6 hours after taking 40 mg of the XR formulation
  • Adults:
    • 12 to 79 ng/mL, 2 hours after taking 20 mg of the IR formulation or 4 to 6 hours after taking 40 mg of the XR formulation
  • Half-life: 2 h
  • Laboratory test result warning threshold: 50 ng/ml
  • At 0.3 mg/kg, children and adults exhibited essentially the same pharmacokinetic parameters (Pharmacokinetic study, human, rat, monkey; full text not available to us, E 2b.)²⁸⁷

• Dexmethylphenidate: (Summary of a consensus guideline, E 4)²⁸⁶

  • 13 to 23 ng/mL, 4 hours after taking 20 mg
  • Half-life: 2 h
  • Laboratory value warning threshold: 44 ng/ml

The following was determined as the provisional therapeutic reference range for methylphenidate in the blood of children and adolescents with ADHD who responded to treatment: (Systematic review with meta-analysis, k = 27, of which k = 10 were used to calculate the range, E 2b.)²⁸⁸

• 1.1 to 16.6 ng/mL, based on the mean ± standard deviation of the maximum concentration (8.8 ± 7.7 ng/mL)
• 7.2 to 11.3 ng/mL according to the 25th/75th percentile

The effect of MPH on ADHD symptoms correlates well with the dose, better with plasma levels, and even better with DAT occupancy in the brain. (Narrative review, E 4.)²⁸⁹ The therapeutic reference ranges provided are population-based statistical values that cannot be applied 1:1 to all patients. To assess neuropsychopharmacotherapy, therefore, the individual therapeutic concentration range for each person with ADHD must be identified. For this purpose, for example, blood levels can be measured after determining the appropriate dose for optimal individual improvement. (Summary of a consensus guideline, E 4)²⁸⁶

3.2. Dose-Dependence of Pharmacokinetics¶

Some studies have found that methylphenidate exhibits nonlinear pharmacokinetics. Based on the AUC, plasma exposure to D-MPH in dogs increased disproportionately with dose. (Animal study, dogs, 13 weeks, author(s) employed by the manufacturer, E 2b.)²⁹⁰ In a patient with narcolepsy, a dose increase from 20 to 40 mg resulted in a 3-fold decrease in oral clearance and a 7-fold increase in the AUC of d-MPH. A similar dose-dependent relationship was observed in 4 healthy subjects (10 to 60 mg). (Pharmacokinetic study, n = 5, E 2b.)²⁹¹ However, the mean total excretion rates (sum of the enantiomers of methylphenidate and its metabolite, ritalinic acid, in urine) remained relatively constant (63 to 78% of the doses), suggesting that the dose-dependent changes in AUC may not be due to a change in intestinal MPH absorption. This could be a consequence of saturation of presystemic elimination. (Pharmacokinetic study, n = 5, E 2b.)²⁹¹

Nevertheless, people with ADHD report quite consistently that the duration of action of MPH medications remains constant across different dose levels. (Experience ADxS)

3.3. Pharmacokinetic Parameters¶

3.4. Plasma Mirror, Effect, and DAT Allocation¶

(E 1b): Plasma levels and the effects of MPH were correlated in:

• Children: Plasma levels correlated significantly with the dose and with improvements in social behavior (as assessed by teachers and parents), but not with cognitive performance. A dose of 1.0 mg/kg twice daily led to discontinuation due to side effects in 5 of 25 children. (Controlled study with fixed dose levels, n = 25, 5 weeks, E 2a.)²⁹⁹
• healthy older adults: A higher plasma AUC following a 20 mg dose of MPH correlated with greater activation in the motor and premotor cortex, temporoparietal cortex, and caudate nucleus during the difficult task (fMRI), with considerable interindividual variability in pharmacokinetics. (Randomized, placebo-controlled crossover study, n = 12, single dose, E 1b.)³⁰⁰
• Adults with ADHD following acute MPH administration: higher plasma levels associated with improvements in concentration, tension, and impulsivity (p = 0.001 to 0.004) (Prospective challenge study, n = 71, single dose, Phase 2b.)¹²⁴
• Children with ADHD, but conversely: higher plasma levels of D- and L-threo-MPH in nonresponders (P3 criterion) (placebo-controlled crossover study, n = 12, single dose, Phase 2b.)¹⁶⁷
• Children in the population PK/PD model of a sustained-release MPH melt-in-the-mouth tablet formulation: maximum reduction in the SKAMP Combined Score of approximately 38 points, EC50 14.24 ng/ml, effective dose directly correlated with body weight (population PK/PD modeling, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)³⁰¹
• Children in the population pharmacokinetic (PD) model: Adult concentration profiles predicted the pediatric pharmacokinetic profiles of various sustained-release formulations (Emax model with time-dependent tolerance) (Modeling meta-analysis, k = 9, author(s) employed by the manufacturer, E 2b.)³⁰²

Plasma levels and the behavioral effects of MPH peaked after 1 to 3 hours; the maximum behavioral effect occurred as plasma levels rose. Due to the high variability in response, one review concluded that measuring plasma levels was not clinically useful and that body weight was not a dose-determining factor. (Narrative review, E 4.)³⁰³ Another review found marked interindividual variability in the dose-response relationship, with it remaining unclear whether this was primarily due to pharmacokinetic or pharmacodynamic factors. Due to stereoselective clearance, drug monitoring would require chiral analysis for d-MPH. (Narrative review, E 4.)³⁰⁴

The MPH concentration varied among individuals in terms of:

• A 25-fold variation in d-MPH concentration per dose among individuals, with intra-individual stability (adults with ADHD and substance use disorder, 30 to 600 mg/day, median 160 mg). In 12 individuals, L-MPH accounted for up to 48% of the total concentration (with low CES1 activity). The non-enantioselective ratio of Ritalin acid to MPH correlated closely with the d-ratio (rs = 0.94) and served as a marker of CES1 activity. (Pharmacokinetic study, n = 28, Phase 2b.)³⁰⁵
• an interindividual coefficient of variation for the saliva-to-serum ratio of 122%, with an intra-individual daily coefficient of variation in saliva of 27.3% (11 to 42%). MPH levels in saliva were approximately 5 times higher than in serum (correlation r = 0.51; pH-dependent r = -0.56). (Clinical study, n = 36 (27 children, 9 adults), E 3.)³⁰⁶
• 0.5 to 43.4 ng/mL (mean 11.6 ± 7.3 ng/mL) at 0.3 to 1.3 mg/kg OROS-MPH (6- to 18-year-olds). The correlation with dose was r = 0.40; 65% of values were below 13 ng/mL. Aripiprazole, risperidone, fluoxetine, and sertraline did not affect the levels. (Retrospective cross-sectional study, n = 100, E 3.)³⁰⁷

(E 1b): MPH’s use of DAT was correlated with plasma levels in:

• In healthy subjects, 10 hours after administration of 36 mg OROS-MPH or 40 mg DBDS-MPH. DAT occupancy was 44.3 ± 11.8% at d-MPH levels of 5.2 ± 2.0 ng/ml, compared with 34.8 ± 12.9% at 3.8 ± 1.2 ng/ml. A plasma difference of 1.4 ng/ml corresponded to approximately 10% DAT occupancy. (Randomized crossover PET study, healthy subjects, n = 21; full text not available to us, E 1b.)³⁰⁸
• Healthy subjects receiving sustained-release dexmethylphenidate (SODAS). Plasma levels and DAT occupancy peaked after 8 hours; DAT occupancy correlated with d-MPH plasma concentration (p < 0.001). In the right caudate nucleus, it was: (PET study, healthy subjects, n = 18; full text not available to us, E 2b.)³⁰⁹
  • 47% after 8 hours with 20 mg
  • 46% after 12 hours with 40 mg (extrapolated)
  • 42% after 10 hours with 30 mg
• Juvenile rhesus monkeys: EC50 for DAT exposure was 21.5 mg/kg orally (95% CI 13.00 to 35.64), compared to 0.25 mg/kg in humans, according to the authors. Maximum plasma concentrations ranged from 3.0 ng/mL (5.6 mg/kg) to 61 ng/mL (32 mg/kg). (Animal study, rhesus monkeys, n = 2, Phase 2b.)³¹⁰