Pharmacotherapy For Treating J. T.’S ADHD Essay
Discussion 7 J. T., who is a Native American male, age 8, is always interrupting his teacher, jumping out of his seat in class, fidgeting relentlessly, and butting into other children’s games. At home, he runs around recklessly and is uncontrollable. His mother comes to the CNP in the Pediatric Clinic and wonders why he will not listen. She is concerned because his grades at school are dropping. After medical evaluation, you find nothing wrong with J. T. physically, and he is taking no other medications. Through questioning, you determine that he has trouble concentrating on his homework, often forgets he has homework, loses pieces of games frequently, and hates to sit and read. His mother is unsure of the time frame over which these behaviors developed, but she thinks it has been since her second child was born 5 years ago. While in your office, J. T. did not seem to be hyperactive or inattentive, but you notice he is easily distracted by people passing in the hallway because the door is slightly ajar. Diagnosis: Attention-Deficit Hyperactive Disorder (ADHD) In this discussion forum: 1. Discuss specific goals for pharmacotherapy for treating J. T.’s ADHD. 2. Discuss the first-line drug therapy for J. T., and why. 3. Pharmacotherapy For Treating J. T.’S ADHD Essay.Discuss monitoring parameters you would institute for J. T.’s parents and his teachers. 4. Discuss specific patient education you would provide to J. T.’s parents based on the prescribed therapy. Remember to respond to at least two of your peers. Please see the Course Syllabus for Discussion Participation Requirements and Grading Criteria
Attention deficit hyperactivity disorder (ADHD) is the most common neurobiological disorder in children, with a prevalence of ~6–7%1,2 that has remained stable for decades2. The social and economic burden associated with patients3, families, and broader systems (healthcare/educational) is substantial, with the annual economic impact of ADHD exceed $30 billion in the US alone4. Efficacy of pharmacotherapy in treating ADHD symptoms has generally been considerable with at least ¾ of individuals benefitting from pharmacotherapy, typically in the form of stimulants5. In this review, we begin by briefly reviewing the history of pharmacotherapy in relation to ADHD, before focusing (primarily) on the state-of-the-field on themes such as biophysiology, pharmacokinetics, and pharmacogenomics. We conclude with a summary of emerging clinical and research studies, particularly the potential role for precision therapy in matching ADHD patients and drug types.
The most common and effective medications are methylphenidates and amphetamines. Atomoxetine and the a-adrenergic agonists are also widely-used, while tricyclics such as modafinil and Wellbutrin are less common and typically less effective6.
First synthesized in 1887, amphetamine (alpha-methylphenethylamine) was not studied clinically until 1927, initially as an artificial replacement for epinephrine7. For several years, it was developed primarily as a bronchodilator, though recognition of stimulant properties subsequently led to a broadening of clinical scope across several dozen conditions7. In 1937, the effects of Benzedrine sulfate treatment were first documented in 30 children (21 boys, 9 girls; 5–14 years old) with a range of behavior disorders. The amphetamine was administered as a treatment for headache, but consequent behavioral changes were marked, including a “drive” to accomplish as much as possible and improvement from a social viewpoint8. A larger follow-up study (n=100) in 19419 was less sweeping in its conclusions, but nevertheless documented “subdued” social impairment in 54% of the children studied10. By this point, amphetamines had been proposed as a treatment for a range of conditions, including schizophrenia, addiction, cerebral palsy, low blood pressure, and seasickness7, with less focus on ADHD10. Pharmacotherapy For Treating J. T.’S ADHD Essay.
It was not until the 1950s that research in stimulant drugs became truly relevant to ADHD (or precursors such as hyperkinetic disease, hyperkinetic impulse disorder, and minimal brain damage11). By then, the amphetamine derivative, methylphenidate, had been synthesized (1944)6,12, and subsequently marketed as ‘Ritalin’11,13. These developments coincided with the waning influence of psychoanalysis, and the belief that behavioral disorders had little or no biological basis11. In 1957, an important study addressing Hyperkinetic impulse disorder in children’s behavior problems, defined hyperactivity as a potentially biological phenomenon, as well as delineating a role for stimulant drugs in its treatment. A surge of studies followed cataloguing the treatment of hyperactive children with stimulant medication, which was maintained as a therapy for the newly-defined Hyperkinetic Reaction of Childhood (DSM-II, 196814) and Attention Deficit Disorder (DSM III, 198015). Currently, stimulant medication is the most common treatment for ADHD, where a diverse catalogue of delivery mechanisms has facilitated development of longer-acting compound preparations. Alternative drug treatments include norepinephrine reuptake inhibitor and α-adrenergic agonists.
While the literature is consistent in confirming the effectiveness of pharmacotherapy in treating ADHD, it is notable that mechanisms of action (MOAs) are generally poorly understood and underdeveloped. Numerous studies have reported differential effects for ADHD medications in terms of associated neurobiology and relevant neurotransmitter systems. Simulants in particular have reportedly affect a plethora of brain regions16, neurotransmitters17, and gene regulators18,19. Atomoxetine and the α-agonists have more targeted effects and this may be reflected in the lower response rates. Table 1, adapted from Elia et al. (2014)6, summarizes approved medications worldwide including methylphenidate, amphetamines, α-adrenergic agonists, and a selective norepinephrine reuptake inhibitor.Pharmacotherapy For Treating J. T.’S ADHD Essay. The most effective pharmacotherapies remain methylphenidate and amphetamine compounds.
|1. Short-Acting Methylphenidate (MPH)|
|MPH||USA, Canada, Europe, China, India, Taiwan, Australia/New Zealand, Africa|
|– MPH||Europe, China, India, Taiwan, Australia/New Zealand, Africa|
|– Ritalin® (Novartis)||USA, Canada|
|– Methylin® (Shinogi)||USA|
|– Metadate® (UCB)||USA|
|– Hytonin (Health Pharmaceutical Co.)||Taiwan|
|– Rubifen (PHARMAC)||Australia/New Zealand|
|– Focalin XR® (Novartis)||USA|
|2. Longer-Acting MPH|
|– Medikinet Retard (Flynn)||Europe|
|– Equasym (Shire)||Europe|
|MPH Sustained Release (SR)||USA, Australia/New Zealand|
|MPH ER (Methylin)||USA|
|Methylphenidate Spheroidal Oral Drug Absorption System (MPH-SODAS)|
|– Ritalin LA® (Novartis)||USA, Europe, Australia/New Zealand|
|– Metadate CD™ (UCB)||USA|
|– Rubinfen SR (Novartis)||Australia/New Zealand|
|Methylphenidate Osmotic Release Oral System (MPH OROS)|
|– Concerta® (Janssen)||USA, Canada, Japan, Europe, Taiwan, Australia/New Zealand|
|– MPH OROS||Central and South America|
|Dexmethylphenidate (DexMPH) Extended Release (XR)|
|– Focalin XR® (Novartis)||USA|
|MPH Transdermal (MTS)|
|– Daytrana® (Noven)||USA|
|MPH XR suspension|
|– Quillivant™ XR (Pfizer)||USA|
|MPH multilayer release|
|3. Short-Acting Amphetamine (AMPH)|
|– Dexedrine® (GSK)||USA, Canada|
|– DextroStat (Wilshire)||USA|
|Mixed AMPH salts|
|– Adderall® (Teva)||USA|
|– Attentin® (Medice)||Europe|
|4. Longer-Acting AMPH|
|Dextro-AMPH sulfate spansules (Dexedrine)||USA, Canada, Australia/New Zealand|
|Mixed AMPH salts XR|
|– Adderall XR (Shire)||USA, Canada|
|– Elvanse||Denmark, Finland, Germany, Liechtenstein, Norway, Spain, Sweden, Switzerland and the United Kingdom|
|– LDX||Canada, Central and South America|
|– Vyvanse® (shire)||US, Canada, Mexico and Australia|
|5. Norepinephrine Reuptake Inhibitor|
|USA, Canada, Central and South America, Europe, Japan, China, India, Taiwan, Australia/New Zealand|
|6. Short-Acting α-Adrenergic Agonists|
|– TenexTM (AH Robins)||USA|
|Clonidine||Europe, India, Australia/New Zealand|
|7. Longer-Acting α-Adrenergic Agonists|
|Guanfacine Extended Release (ER)|
|– Intuiv® (Shire)||USA|
|Clonidine Extended Release (ER)|
|– Kapvay® (Shionogi)||USA|
Relative to other psychiatric diseases, ADHD is often considered a poster-child in terms of the effectiveness of drug treatments. Indeed, a large-scale meta-analysis by Leucht et al. (2012) that included 16 drugs in 8 psychiatric disorders, showed that methylphenidate and amphetamine are among the most effective psychotropics, with only lithium (major depressive disorder, maintenance therapy) showing comparable results. The same study reported a less robust effect size for atomoxetine/ADHD. In total, between 75% and 90% of patients have been reported to respond to some form of pharmacotherapy, although many patients do not necessarily respond to the first drug regimen. Pharmacotherapy For Treating J. T.’S ADHD Essay. Methylphenidate and amphetamines are most widely-prescribed for ADHD, and clinical trials have repeatedly demonstrated their efficacy across short- and long-acting preparations, and across ages ranging from preschool to adulthood20–24.
Table 2 (Elia et al., 2014)6 summarizes the effect size of relevant ADHD treatments. In addition to stimulants, atomoxetine and α-adrenergic agonists are also effective in managing ADHD symptoms, though, as outlined, relevant effect sizes are comparably smaller to those of stimulants. A caveat being that often patients prescribed atomoxetine/α-adrenergic agonists may already have failed to respond to stimulants, so it may not be a strictly representative cohort.
|ADHD Medications||Other Psychiatric Medications|
|0.9+||Amphetamine: ~1.0 (0.91–1.10)|
|0.7–0.79||Methylphenidate: ~0.78 (0.64–0.91)|
|0.6–0.69||Atomoxetine: 0.65 (0.52–0.82)|
|0.5–0.59||Clonidine: 0.58||Second-gen. antipsychotics (SGA)/Haloperidol, Schizophrenia: 0.51–0.53|
|0.4–0.49||Guanfacine (extended release): ~0.5 (0.43–0.52)||SGA/Mood Stabilizers, Bipolar: 0.40–0.53|
|0.3–0.39||Selective serotonin reuptake inhibitors, OCD: 0.31–0.41; Antidepressants, MDD: 0.31–0.32|
Beyond ADHD core symptoms, pharmacotherapy has been associated with improved quality of life25, decreased risk of developing depression26,27 and anxiety/disruptive disorders over a 10 year period27, paralleled by improved grade retention27. A 2012 study of 25,656 ADHD patients from the Swedish national register compared criminal convictions across a three-year period and found a significant decrease in the rate of criminality while patients were ADHD medication versus the same patients unmedicated28.
The mechanisms by which those medications listed in Table 1 impact upon ADHD symptoms are poorly understood. Several studies report a role for methylphenidate in inhibiting dopamine transporters in the cortex and striatum29,30. The same drug may also inhibit the norepinephrine transporter in the cortex30. The MOA may relate to amphetamine stimulating leakage of dopamine and norepinephrine into the synaptic cleft. In turn, this may inhibit their degradation and inactivate the storage protein pump. Ultimately, this would increase the extracellular availability of both neurotransmitters and also extracellular serotonin31. Pharmacotherapy For Treating J. T.’S ADHD Essay.
Improvements in attention associated with taking methylphenidate are correlated with increased dopamine levels in the ventral striatum, prefrontal cortex (PFC), and temporal cortex32. Methylphenidate administration has also been associated with normalizing underactive frontocingulate networks33 and striatal areas34 and increased frontoparietal connectivity for working memory35. Other neurobiological changes observed in relation to methylphenidate administration include enhanced error-detection associated with the dorsal anterior cingulate cortex and inferior parietal lobe36, and optimized speed-of-reaction related to (pre-) motor cortex37. A number of other gross neurobiological effects have been associated with taking methylphenidate, including increased activation in the caudate, cerebellum, midbrain, substantia nigra, thalamus38, and many others. Wong et al. (2012)35 report increased functional connectivity in the anterior cingulate, ventrolateral PFC, and precuneus, which is also associated with working memory.
Atomoxetine increases the availability of norepinephrine (noradrenaline) and dopamine in the PFC39, selectively inhibiting relevant transporters presynaptically. It also an NMDA receptor antagonist, thereby altering glutamatergic transmission40. Unlike stimulants, atomoxetine is not strongly associated with striatal effects, and is less likely to be abused (full effect also takes 4–6 weeks). Neurobiological correlates of atomoxetine administration include increased regional cerebral blood flow in the cerebellar cortex, and decrease blood flow to the midbrain, substantia nigra and thalamus38. Enhanced inhibitory control following atomoxetine has also been associated with increased activation of the right inferior frontal gyrus41.
Guanfacine inhibits cyclic AMP, closing hyperpolarization-activated (HCN) cyclic nucleotide-gated channels and increasing functional connectivity in the PFC. By blocking/knocking-down HCN1 channels in the PFC therefore, guanfacine can improve working memory42. Guanfacine has been shown to increase activation in the dorsolateral PFC. It is noteworthy that glutamatergic synapses have heteroceptors that are inhibitory α2A-adrenoceptors43, and it is possible (though admittedly speculative) that clonidine and guanfacine are effective by reducing presynaptic glutamate release in the PFC. Pharmacotherapy For Treating J. T.’S ADHD Essay. This hypothesis is supported by a recent study by Miller et al. (2014)44, which showed abnormal glutamate signaling in the signaling in PFC and striatum of the spontaneously hypertensive rat model of ADHD. The potential role for glutamatergic medication in treating ADHD is discussed further below.
As illustrated in Table 3, ADHD medications have been associated with a range of common and rare adverse effects45, that correlate with age/developmental-stage21. While many adverse events are often transient and dose-dependent46, effects such as appetite loss may persist for years47. Adverse events may also be genotype-specific, with, for example, CYP2D6 poor metabolizers at greater risk with atomoxetine48.
|Medication||Common Adverse Effects||Rare Adverse Effects|
|Anorexia, weight loss (12–13%)
Abdominal Pain (6–12%)
Emotional lability (2–10%)
Decreased appetite (11%)
Weight loss (2%)
Dry mouth (20%)
Dysuria/urinary retention (3–7%)
QT prolongation (blocked hERG channels)
|α-adrenergic agonists||Somnolence (38%)
Abdominal pain (10%)
Decreased BP (6%)
Decreased appetite (5%)
Dry mouth (4%)
Increased urinary frequency
As outlined, cardiovascular effects are among the most serious adverse events. Sudden death, reported in four children taking clonidine, are particularly concerning, but investigations into these deaths attribute likely cause to pre-existing cardiac conditions and concomitant drug treatment6. Bradycardia, however, has been consistently reported with clonidine – in up to 17.5% of patients on mono- or combined-therapy with stimulants, vs. 3.4% in non-users49.Pharmacotherapy For Treating J. T.’S ADHD Essay. The same study also found drowsiness to be a widespread effect of clonidine use, but this may resolve in <2 months. A 2012 study of antipsychotics by Winterstein et al. (2012)50 documented 1,219,847 children and 95 events (66 excluding ventricular arrhythmia), and reported an adjusted odds ratio of 0.62 for stimulant vs. non-stimulant use. This corresponds to corresponding an adjusted incidence rate of 2.2 vs. 3.5 per 100 000 patient years for stimulant use vs. non-use, and is essentially negligible.
With atomoxetine, liver toxicity is rare but not trivial. Bangs et al. (2008)51 studied 7,961 children and adult patients taking atomoxetine during clinical trials, and reported 41 patients with documented hepatobiliary events, but none of which progressed to liver failure. The same study identified 351 spontaneous adverse hepatic events, of which three suggested atomoxetine as a probable cause (of the remainder, 69 were categorized as unrelated to atomoxetine, 133 as confounding factors, 146 too little information). One of these three had a positive re-challenge. Additionally, Lim et al. (2006) 52 presented cases studies of two children with acute hepatitis following atomoxetine. In one, no competing diagnosis was found, and liver injury resolved by discontinuing atomoxetine. In the second, evaluation suggested type 1 autoimmune hepatitis, which also ameliorated with discontinuation and concomitant immunosuppressive therapy.
Self-injury/ideation is another adverse event on the more serious spectrum. Such ideation has been reported in ~1.5% of patients prescribed atomoxetine or stimulants, and monitoring for such effects is warranted. Additional limitations include generally short-half lives that diminish behavioral efficacy to several hours/day for the stimulants and drug interactions via P450-2D6 for atomoxetine.
Several reviews have cataloged the role of genetic variants in mediating responses to ADHD medication, indicating mixed and inconclusive results53,54, and suggesting that, similar to the disease itself, drug response is a highly complex trait.
Indeed, methylphenidate has been reported (in rats) to upregulate expression of >700 genes in the striatum involved in neural/synaptic plasticity including neurotransmitter receptors, proteins responsible for transport and anchoring, and many others55. Thus, a reason why stimulants show efficacy in most individuals may be due to the fact that they affect expression in numerous genes throughout the brain, thus impacting on potentially numerous variants. For similar reasons, response rates may be lower for the more selective medications such as atomoxetine and α-adrenergic agonists, potentially with fewer variants involved. Pharmacotherapy For Treating J. T.’S ADHD Essay.
The majority of PGx-based studies have focused on existing ADHD medications, primarily methylphenidate, with the goal of identifying specific biomarkers of drug response, which are reviewed briefly here (see also Bruxel et al., 201456). One exception to this approach is a study from our group, which has used results from genomics analyses to identify novel drug targets for a genome-stratified ADHD sub-cohort.
Interactions between DAT1 genotypes and methylphenidate response are among the most-widely studied in terms of ADHD and PGx. The dopamine active transporter (DAT) protein encoded by DAT1 is widely expressed in the dopaminergic system, particularly in projections to the nucleus accumbens and striatum57. Several variable number tandem repeats (VNTRs) have been identified for DAT1, with the 9-repeat and 10-repeat alleles. Froehlich et al (2011)58 reported that 10R carriers vs. non-carriers are poorer responders to methylphenidate, with an effect size of 0.59–0.64 (though n=89). Pasini et al. (2013)59 compared responses of 108 drug-naïve patients to methylphenidate treatment across a 24-week period. The sample was stratified into 9R/9R, 9R/10R, and 10R/10R sub-cohorts, with various outcomes (response inhibition, working memory, planning) assessed longitudinally. Patients with the 10R genotype had consistently improved response inhibition, which was not seen after therapy was discontinued. Improvement in planning and working memory were also noted and maintained, but it is again difficult to draw firm conclusions given the sample size. This would seem substantiated by a meta-analysis by Kambeitz et al., 2014 (n=1572)60, which found no evidence of a genotype-specific response to methylphenidate treatment (P>0.5). Similarly, VNTRs in the dopamine receptor D4 (DRD4) have been studied, again with no strong evidence of a genotype-specific response to methylphenidate56.
ADHD PGx interactions have also been studied in relation to the norepinephrine transporter gene (NET1), though again results are inconclusive. Kim et al. (2010)61 compared methylphenidate response between A-3081T (rs28386840) and G1287A (rs5569) genotypes in 112 Korean children, where Clinical Global Impression-Improvement scores were higher in the former (61.4%) compared to the latter (37.9%), though again the study is underpowered and was not replicated by a subsequent study62.Pharmacotherapy For Treating J. T.’S ADHD Essay. Several other studies of NET1 effects in different Asian populations have also been reported and are similarly inconclusive.
A large range of other proposed ADHD-PGx candidate genes include ADRA2A, COMT, TPH2, DBH, 5-HTT, BDNF, SNAP25, and LPHN3 (review at Bruxel et al., 201456), but as yet none constitute a stand-out model for targeted/precision intervention. Below, we discuss a different approach to the PGx model, in which genomics results can be used to guide development of novel therapeutics (as opposed to stratify response to existing medications).
A recent study sequenced 202 genes (including dopaminergic, adrenergic, glutamatergic, histaminergic and cholinergic receptor genes-considered potential drug targets) in approximately 14,000 individuals (not ADHD), and discovered that 95% of genetic variants were not common but rare (occurring in less than 0.5% of the population) with 74% found in only one or two individuals63. This further suggests that—not only for ADHD but for other disorders as well—pharmacotherapeutic targets of the future are likely to focus on rarer genetic variants.
To this end, a large-scale, genome-wide study from our group compared copy number variations (CNVs) in ADHD cases (3,500) vs. controls (~13,000) revealed that rare, recurring CNVs impacting specific GRM genes (i.e. GRM1, GRM5, GRM7, and GRM8) encoding for metabotropic glutamate receptors (mGluRs) were found in ADHD patients at significantly higher frequencies compared to healthy controls64. The large effect sizes (with odds-ratios of >15) suggest that these mutations likely are highly penetrant for their effects on ADHD. Single cases with GRM2 and GRM6 deletions were also observed that were not found in controls.
When genes in the signaling pathway of GRM genes (i.e. a GRM/mGluR-network) were assessed, significant enrichment of CNVs was found to reside within this network in ADHD cases compared to controls. Our group recently identified 228 genes within the GRM gene networks based on the merged human interactome provided by the Cytoscape Software18. A network analysis of the mGluR pathway found that in the EA population of approximately 1,000 cases and 4,000 controls, genes involved with GRM signaling or their interactions are significantly enriched for CNVs in cases (P = 4.38×10−10), collectively impacting ~12% of the ADHD cases, corrected for control occurrence (Figure 1B). These data suggest that GRMs may serve as critical hubs that coordinate highly-connected modules of interacting genes, many of which harbor CNVs and are enriched for synaptic and neuronal biological functions. Thus, we have identified several rare recurrent CNVs that are overrepresented in multiple independent ADHD cohorts that impact genes involved in glutamatergic neurotransmission, which is essential for the developing brain and normal brain function. These results suggest that variations involving mGluR gene networks of the brain contribute to the genetic susceptibility of ADHD. Further, disrupted mGluR signaling/activity in ADHD in a sub-cohorts can be identified based on genetic profiling of their genes within this GRM-network and selectively drug-targeted. Pharmacotherapy For Treating J. T.’S ADHD Essay.