Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review

In the paper

“Circadian rhythm regulates some biological activities such as sleep and mood [113] through various mechanisms such as the transcription-translation feedback loop (TTFL), which includes two transcription activators: circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1). Both activators create a heterodimer, which inhibits the transcription of repressor pro”

What the sources say

• ?Not checked — no full text of the sourcecites [113] Lee YA, Goto Y. Habenula and ADHD: convergence on time. Neurosci Biobehav Rev. 2013;37(8):1801–9. source
• Disputed

  Split into 3 atoms — 2 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  cites [114] Xie Y, Tang Q, Chen G, et al. New insights into the circadian rhythm and its related diseases. Front Physiol. 2019;10:682. sourceExperimental — accuracy not yet measured

In the paper

“Some stimulants, such as amphetamines, and non-stimulants, such as atomoxetine, have been reported to be substrates of cytochrome P450s, and their performance has been linked to CYP2D6 genotype [41, 42].”

What the sources say

• Partly supported

  Section 5.2 says atomoxetine is metabolized by CYP2D6 and that poor metabolizers may have different therapeutic outcomes or adverse effects. Section 5.1 says CYP2D6 metabolizes amphetamine, but only suggests its metabolism may vary across populations; it does not link amphetamine's clinical performance to CYP2D6 genotype. Page numbers are not available in our copy. (LLM, conf=0.86)

  cites [41] Kam H, Jeong H. Pharmacogenomic biomarkers and their applications in psychiatry. Genes. 2020;11(12):1445. sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [42] FDA. Table of pharmacogenomic biomarkers in drug labeling. https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling. Accessed Aug 2021.

In the paper

“Moreover, ADHD is commonly associated with other comorbid diseases (depression, anxiety, bipolar disorder, etc.) [5]”

What the sources say

• Partly supported

  The Systematic Review of the Literature section says comorbid disorders are extremely common in ADHD, affecting an estimated 50–70% of individuals. It does not identify depression, anxiety, or bipolar disorder as examples, so the cited paper supports the general association but not the specific list. (LLM, conf=0.88)

  cites [5] Posner J, Park C, Wang Z. Connecting the dots: a review of resting connectivity MRI studies in attention-deficit/hyperactivity disorder. Neuropsychol Rev. 2014;24(1):3–15. sourceExperimental — accuracy not yet measured

In the paper

“Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterised by a symptomatology based on persistent inattention, hyperactivity, and impulsivity that has been considered a progressively ceaseless condition [1].”

What the sources say

• Supported

  The Adult ADHD section describes ADHD as a common, childhood-onset, chronic disorder characterized by inattentiveness, impulsivity, and hyperactivity. It also reports that follow-up studies documented persistence into adulthood, supporting the citing sentence’s reference to an enduring condition. (LLM, conf=0.94)

  cites [1] Franke B, Faraone SV, Asherson P, et al. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry. 2012;17(10):960–87. source

In the paper

“Several risk genes have been found in the human genome [59], but only a limited number of small impact size ADHD genes have been identified [60].”

What the sources say

• Supported

  The citation [60] attaches to the second clause. The GWAS section reports only 12 genome-wide significant loci covering 16 genes, and the Heritability in ADHD section links the small number of hits to rare alleles or low effect sizes. Together, these support the claim that relatively few ADHD-associated genes with small effects had been identified. (LLM, conf=0.89)

  cites [59] Grimm O, Kranz TM, Reif A. Genetics of ADHD: what should the clinician know? Curr Psychiatry Rep. 2020;22(4):18. source
• ?Could not verify

  Citation [60] is attached to the claim that only a limited number of small-effect ADHD genes have been identified. The retrieved passages from our indexed copy contain bibliographic information and ADHD-related keywords, but none addresses the number or effect size of identified genes (searched for genetic factors, ADHD risk genes, and small effect size). (LLM, conf=0.70)

  cites [60] Verlaet AA, Noriega DB, Hermans N, Savelkoul HF. Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry. 2014;23(7):519–29. sourceExperimental — accuracy not yet measured

In the paper

“several biological pathways have been suggested to potentially affect MPH mechanisms through patient genotype, mostly concerning monoamine pathways [43–48].”

What the sources say

• Partly supported

  The Discussion (page unavailable) suggests that genetic variants in neurotransmitter-release and GABA-transmission pathways could affect MPH treatment response. The Introduction identifies dopamine and norepinephrine transporters as MPH’s main direct targets, but the paper does not establish that genotype-related pathways are mostly monoamine pathways; its Discussion emphasizes effects beyond dopamine and norepinephrine. (LLM, conf=0.84)

  cites [43] da Silva BS, Leffa DT, Beys-da-Silva WO, et al. Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response. Transl Psychiatry. 2019;9(1):308. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [44] Angyal N, Horvath EZ, Tarnok Z, et al. Association analysis of norepinephrine transporter polymorphisms and methylphenidate response in ADHD patients. Prog Neuropsychopharmacol Biol Psychiatry. 2018;84(Pt A):122–8. source
• Supported

  The Introduction (page unavailable) says that many ADHD candidate genes play a role in psychostimulant mechanisms and may be associated with treatment response. The Method’s gene table (page unavailable) includes numerous dopamine, norepinephrine, and serotonin genes alongside genes from other pathways, and the Discussion reports genotype associations with MPH response. Together, these passages support the hedged claim. (LLM, conf=0.88)

  cites [45] Gomez-Sanchez CI, Carballo JJ, Riveiro-Alvarez R, et al. Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects. Sci Rep. 2017;7(1):10391. source
• Supported

  The Discussion says the candidate-gene studies focused mainly on noradrenergic and dopaminergic genes because MPH is suspected to act through those pathways. The Results also list polymorphisms in these and other genes examined for associations with MPH adverse events in children and adolescents. This supports the claim as a suggestion about genotype-related pathways, not an established mechanism. (LLM, conf=0.84)

  cites [46] Joensen B, Meyer M, Aagaard L. Specific genes associated with adverse events of methylphenidate use in the pediatric population: a systematic literature review. J Res Pharm Pract. 2017;6(2):65–72. source
• Supported

  The Introduction says genetic factors may influence MPH response and describes both metabolic and monoaminergic mechanisms. It specifically links polymorphisms in monoaminergic genes to stimulant response, while noting that the evidence is conflicting; the Results also discuss variants in other pathways. (LLM, conf=0.92)

  cites [47] Myer NM, Boland JR, Faraone SV. Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD. Mol Psychiatry. 2018;23(9):1929–36. source
• Supported

  The Introduction (page not provided) describes dopamine- and noradrenergic-system genes as associated with methylphenidate response, and explains that methylphenidate acts on dopamine and norepinephrine transporters. This supports the hedged claim that genotype-related monoamine pathways may affect how methylphenidate works. (LLM, conf=0.88)

  cites [48] Yuan D, Zhang M, Huang Y, Wang X, Jiao J, Huang Y. Noradrenergic genes polymorphisms and response to methylphenidate in children with ADHD: a systematic review and meta-analysis. Medicine. 2021;100(46):e27858. source

In the paper

“In this sense, gender may play a role in ADHD aetiology with an incidence rate of 2:1 in boys versus girls [55].”

What the sources say

• Partly supported

  The Epidemiology section reports that more boys than girls are diagnosed with ADHD, at a 2:1 ratio. It does not describe that ratio as an incidence rate or establish that gender plays a role in ADHD’s aetiology; the Risk factors section discusses other potential causes. (LLM, conf=0.89)

  cites [55] Cabral MDI, Liu S, Soares N. Attention-deficit/hyperactivity disorder: diagnostic criteria, epidemiology, risk factors and evaluation in youth. Transl Pediatr. 2020;9(Suppl 1):S104–13. sourceExperimental — accuracy not yet measured

In the paper

“The ADHD symptomatology interferes with subject function and development according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria [2] impairing daily function [3, 4].”

What the sources say

• ?Could not verify

  The DSM-5 CLASSIFICATION passage says ADHD is grouped with autism spectrum disorder among neurodevelopmental disorders. Our copy does not state that ADHD symptoms interfere with functioning or development; searches for ADHD, functional impairment, and diagnostic criteria did not find that point. No page number was provided for the passage. (LLM, conf=0.73)

  cites [2] Regier DA, Kuhl EA, Kupfer DJ. The DSM-5: classification and criteria changes. World Psychiatry. 2013;12(2):92–8. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [3] Feldman HM, Reiff MI. Clinical practice. Attention deficit-hyperactivity disorder in children and adolescents. N Engl J Med. 2014;370(9):838–46. source
• ?Not checked — no full text of the sourcecites [4] Dalsgaard S, Leckman JF, Mortensen PB, Nielsen HS, Simonsen M. Effect of drugs on the risk of injuries in children with attention deficit hyperactivity disorder: a prospective cohort study. Lancet Psychiatry. 2015;2(8):702–9. source

In the paper

“and in adult age it is a risk factor for various mental disorders [6, 7].”

What the sources say

• Partly supported

  The Results (section 3.3, p. 3) report substantially higher rates of mood, anxiety and substance use disorders among adults with ADHD than among reference patients. The Discussion (section 4.2, p. 5) says ADHD *may* be a risk factor for these comorbidities; the citing sentence states that conclusion without the paper’s qualification. (LLM, conf=0.84)

  cites [6] Libutzki B, Ludwig S, Jacobsen RH, Reif A, Hartman CA. Direct medical costs of ADHD and its comorbid conditions on basis of a claims data analysis. Eur Psychiatry. 2019;58:38–44. sourceExperimental — accuracy not yet measured
• Supported

  The Psychiatric Comorbidity section (page not supplied) reports high rates of adult antisocial disorders among adults with ADHD. Its Mood & Anxiety subsection says ADHD increases the likelihood of depression at least two-fold and describes high rates of anxiety symptoms, supporting the broad risk-factor claim. (LLM, conf=0.88)

  cites [7] Wilens TE, Spencer TJ. Understanding attention-deficit/hyperactivity disorder from childhood to adulthood. Postgrad Med. 2010;122(5):97–109. source

In the paper

“ADHD, as with other psychiatric disorders, is not easy to diagnose. In this sense, their diagnosis has been criticized because it is not based on a biological testing, and it has been considered subjective [14].”

What the sources say

• Supported

  The “How is ADHD diagnosed?” section explicitly says that ADHD diagnosis has been criticized as subjective because it is not based on a biological test. The paper calls that criticism unfounded, but the citing sentence attributes the existence of the criticism, not its validity, to the source. (LLM, conf=0.95)

  cites [14] Faraone SV, Banaschewski T, Coghill D, et al. The World Federation of ADHD International Consensus Statement: 208 evidence-based conclusions about the disorder. Neurosci Biobehav Rev. 2021;128:789–818. source

In the paper

“no clear guidelines have been developed and there is still much to understand in this regard [50].”

What the sources say

• Supported

  The Current Challenges and Future Directions section contrasts a published atomoxetine pharmacogenomic guideline with the limited research on methylphenidate and says understanding of ADHD medication response remains imperfect. The Conclusions state that personalized predictive ADHD care has not yet arrived and call for further research. Together, these support the paraphrase about the lack of clear MPH pharmacogenomic guidance and remaining uncertainty; page numbers were not available in our copy. (LLM, conf=0.86)

  cites [50] Elsayed NA, Yamamoto KM, Froehlich TE. Genetic influence on efficacy of pharmacotherapy for pediatric attention-deficit/hyperactivity disorder: overview and current status of research. CNS Drugs. 2020;34(4):389–414. source

In the paper

“However, other studies using single-nucleotide polymorphism (SNP) analysis have estimated that SNP-based heritability ranged between 10% and 28% [57].”

What the sources say

• Partly supported

  The Discussion reports an ADHD SNP-based heritability estimate of 0.28 (28%). The Results describe variation between ADHD subsets, but the passages found do not give a 10% estimate or establish a 10%–28% range. (LLM, conf=0.87)

  cites [57] Lee SH, Ripke S, Neale BM, et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45(9):984–94. sourceExperimental — accuracy not yet measured

In the paper

“Most of these conditions/disorders usually appear later in development and can manifest as a result of ADHD, but this is not always the case with early stage behavioural problems directly related to ADHD [58].”

What the sources say

• Partly supported

  In “The overlap of ADHD with other developmental and psychiatric disorders” (page not provided), the review says some comorbid problems can present later and might arise as a consequence of ADHD, with an exception for early-onset conduct problems. It does not say that most comorbid conditions usually appear later; the claim overstates that part. (LLM, conf=0.86)

  cites [58] Thapar A, Cooper M, Eyre O, Langley K. What have we learnt about the causes of ADHD? J Child Psychol Psychiatry. 2013;54(1):3–16. sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, ADHD has demonstrated a high degree of comorbidity of other psychological and mental conditions such as insomnia, anxiety, conduct disorder, sleep disturbance, oppositional defiant disorder, binge eating disorder, tic disorder, bipolar disorder, personality disorder, drug and substance dependence and mood disturbances, among others [72, 74].”

What the sources say

• ?Not checked — no full text of the sourcecites [72] Wu J, Xiao H, Sun H, Zou L, Zhu LQ. Role of dopamine receptors in ADHD: a systematic meta-analysis. Mol Neurobiol. 2012;45(3):605–20. source
• Partly supported

  The “Adult ADHD-Associated Cognitive Impairment and Comorbidities” section (page unavailable) associates ADHD with depression, anxiety, and alcohol/drug dependency; its Depression and Anxiety subsections give further support for those conditions. The copy does not support the sentence’s additional examples, including insomnia, conduct disorder, oppositional defiant disorder, binge eating disorder, tic disorder, bipolar disorder, and personality disorder. (LLM, conf=0.90)

  cites [74] Ivanchak N, Fletcher K, Jicha GA. Attention-deficit/hyperactivity disorder in older adults: prevalence and possible connections to mild cognitive impairment. Curr Psychiatry Rep. 2012;14(5):552–60. sourceExperimental — accuracy not yet measured

In the paper

“Environmental factors such as chemical contaminants (pesticides and harmful agricultural chemicals) may promote the neural structure impairments involved in ADHD [58].”

What the sources say

• Partly supported

  The Environmental toxins section says organic pollutants may damage neural systems implicated in ADHD. The Pesticides section reports associations between pesticide exposure and ADHD-related outcomes, but does not show that pesticides cause structural neural impairments; it also notes inconsistent findings. No page numbers are available in our copy. (LLM, conf=0.84)

  cites [58] Thapar A, Cooper M, Eyre O, Langley K. What have we learnt about the causes of ADHD? J Child Psychol Psychiatry. 2013;54(1):3–16. sourceExperimental — accuracy not yet measured

In the paper

“This system is involved in motivation and reward/avoidance behaviours; in this sense, lower DA levels in the PFC could lead to less motivation, resulting in inattention. This might also be the reason for the promiscuous reward-seeking behaviours found in hyperactive-impulsive patients with ADHD [83].”

What the sources say

• Partly supported

  The Introduction links prefrontal dopamine to cognitive function, while the “Saliency Enhancing” Model links dopamine-mediated motivation to attention. But those passages concern different pathways: the paper does not say that low dopamine in the PFC reduces motivation or causes inattention, or that it explains promiscuous reward-seeking in hyperactive-impulsive ADHD. (LLM, conf=0.84)

  cites [83] Engert V, Pruessner JC. Dopaminergic and noradrenergic contributions to functionality in ADHD: the role of methylphenidate. Curr Neuropharmacol. 2008;6(4):322–8. sourceExperimental — accuracy not yet measured

In the paper

“Regarding the influence of psychosocial adversity in ADHD disorder development, extreme parental discord, poor socioeconomic status, paternal violence, inconsistent parent–child relationships, maternal psychiatric disability, parental disapproval, family anxiety and foster placement have been reported as family random factors associated with behavioural disorders in childhood [58, 70].”

What the sources say

• Partly supported

  The ‘Family adversity and early care-giving’ section reports associations of low income, family adversity, maltreatment and family conflict with child mental health problems, including ADHD. It does not report the full list of specific factors in the claim, such as paternal violence, maternal psychiatric disability and parental disapproval. It also cautions that, except for rare extreme early deprivation, psychosocial adversity has not clearly been shown to cause ADHD. (LLM, conf=0.86)

  cites [58] Thapar A, Cooper M, Eyre O, Langley K. What have we learnt about the causes of ADHD? J Child Psychol Psychiatry. 2013;54(1):3–16. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [70] Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366(9481):237–48. source

In the paper

“highlighting prenatal, perinatal and postnatal difficulties, psychological adversities, exposure to chemical contaminants, or iron deficiency as factors that increase the probability of developing ADHD [54]”

What the sources say

• Partly supported

  The Introduction’s “environmental basis of ADHD” section (page unavailable) links prenatal and perinatal factors to ADHD and identifies postnatal social deprivation and iron deficiency as possible contributors. It does not identify exposure to chemical contaminants as an ADHD risk factor, and its statements about social deprivation and iron deficiency are narrower and more tentative than the citing sentence. (LLM, conf=0.86)

  cites [54] Curatolo P, D’Agati E, Moavero R. The neurobiological basis of ADHD. Ital J Pediatr. 2010;36(1):79. sourceExperimental — accuracy not yet measured

In the paper

“NE, also known as noradrenaline (NA), is an important NT in behaviour control, playing a key role in high-level cognitive processes such as working memory and inhibitory response, which appear to be disrupted in ADHD [79], producing irritability and anxiety [85].”

What the sources say

• ?Not checked — no full text of the sourcecites [79] Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiat. 2011;69(12):e145–57. source
• Partly supported

  The Discussion (page not provided) says overactivity of the noradrenergic system could manifest as anxiety and irritability. That supports the symptoms linked to citation [85], but the paper does not establish that disrupted working memory or inhibitory responses in ADHD produce them; it also presents the symptom link as a possibility, not a certainty. (LLM, conf=0.83)

  cites [85] Yamamoto K, Shinba T, Yoshii M. Psychiatric symptoms of noradrenergic dysfunction: a pathophysiological view. Psychiatry Clin Neurosci. 2014;68(1):1–20. sourceExperimental — accuracy not yet measured

In the paper

“Slower maturation or decreased size of the PFC and also diminished PFC, caudate or cerebellum activation have been found in patients with ADHD [77, 78].”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Valera EM, Faraone SV, Murray KE, Seidman LJ. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiat. 2007;61(12):1361–9. source
• Partly supported

  The Discussion reports that cortical maturation delay in ADHD was most prominent in the lateral prefrontal cortex and describes prefrontal hypoactivation in children with ADHD. It does not establish decreased PFC size or diminished caudate or cerebellar activation; the study measured cortical thickness and its maturation, not activation in those regions. (LLM, conf=0.86)

  cites [78] Shaw P, Eckstrand K, Sharp W, et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci USA. 2007;104(49):19649–54. sourceExperimental — accuracy not yet measured

In the paper

“ADHD disorder is usually accompanied by other comorbid conditions. In fact, patients with ADHD are frequently diagnosed with another neuropsychiatric conditions, which can mask ADHD [71].”

What the sources say

• Partly supported

  In “A Brief Summary on ADHD” (page unavailable), the paper says comorbidities such as depression, anxiety, and conduct disorder are common in children with ADHD. It does not say that patients are frequently diagnosed with another condition or that such a diagnosis can mask ADHD, and its statement about comorbidity is limited to children. (LLM, conf=0.87)

  cites [71] Rothenberger LG. Molecular genetics research in ADHD: ethical considerations concerning patients’ benefit and resource allocation. Am J Med Genet B Neuropsychiatr Genet. 2012;159B(8):885–95. sourceExperimental — accuracy not yet measured

In the paper

“Reduced maternal thyroid capacity, poor maternal wellness, maternal age, post-maturity of the foetus, long working hours, maternal stress, foetal stress, prenatal exposure to alcohol and tobacco, and antepartum haemorrhage are prenatal factors that could influence ADHD development [54, 58, 65].”

What the sources say

• Partly supported

  The Introduction’s “The environmental basis of ADHD” section links prenatal alcohol exposure and maternal smoking to ADHD-related outcomes, and mentions pregnancy and birth complications generally. It does not identify reduced thyroid capacity, poor maternal wellness, maternal age, post-maturity, long working hours, maternal or foetal stress, or antepartum haemorrhage as factors. (LLM, conf=0.90)

  cites [54] Curatolo P, D’Agati E, Moavero R. The neurobiological basis of ADHD. Ital J Pediatr. 2010;36(1):79. sourceExperimental — accuracy not yet measured
• Partly supported

  The “Pre and perinatal risks” section associates maternal smoking and stress with offspring ADHD and reports a less consistent association for prenatal alcohol exposure. It does not identify reduced maternal thyroid capacity, poor maternal wellness, maternal age, post-maturity, long working hours, foetal stress, or antepartum haemorrhage as ADHD risks; it discusses prematurity, not post-maturity. The review also cautions that causation has not been established. (LLM, conf=0.88)

  cites [58] Thapar A, Cooper M, Eyre O, Langley K. What have we learnt about the causes of ADHD? J Child Psychol Psychiatry. 2013;54(1):3–16. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [65] D’Onofrio BM, Van Hulle CA, Waldman ID, Rodgers JL, Rathouz PJ, Lahey BB. Causal inferences regarding prenatal alcohol exposure and childhood externalizing problems. Arch Gen Psychiatry. 2007;64(11):1296–304. source

In the paper

“Obesity and nutritional deficiencies (deficiency in the intake of essential fatty acids), lower serum levels of ferritin, and iron deficiency, as postnatal factors, have been suggested to promote abnormalities in the brain and thereby influence the onset of ADHD [66–69].”

What the sources say

• ?Not checked — no full text of the sourcecites [66] Alwan NA, Hamamy H. Maternal iron status in pregnancy and long-term health outcomes in the offspring. J Pediatr Genet. 2015;4(2):111–23. source
• ?Not checked — no full text of the sourcecites [67] San Maurotín I, Blumenfeld Olivares JA, Garicano Vilar E, et al. Nutritional and environmental factors in attention-deficit hyperactivity disorder (ADHD): a cross-sectional study. Nutr Neurosci. 2018;21(9):641–7. source
• Partly supported

  The Introduction reports an association between obesity and ADHD, which supports only the broad link between them. It does not describe obesity as causing brain abnormalities or influencing ADHD onset, and the searched passages do not address ferritin, iron deficiency, or essential fatty acid deficiency as postnatal factors. (LLM, conf=0.78)

  cites [68] Tong L, Xiong X, Tan H. Attention-deficit/hyperactivity disorder and lifestyle-related behaviors in children. PLoS ONE. 2016;11(9): e0163434. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction links prenatal and postnatal iron deficiency to impaired neurodevelopment, and the Discussion proposes mechanisms by which low iron and ferritin might relate to ADHD. The Conclusions report lower ferritin in children with ADHD and an association between iron deficiency and ADHD, while cautioning that the predominantly cross-sectional evidence cannot establish directionality. This paper does not support the sentence’s claims about obesity or essential fatty acid deficiency. Page numbers are not provided in our copy. (LLM, conf=0.88)

  cites [69] Tseng PT, Cheng YS, Yen CF, et al. Peripheral iron levels in children with attention-deficit hyperactivity disorder: a systematic review and meta-analysis. Sci Rep. 2018;8(1):788. sourceExperimental — accuracy not yet measured

In the paper

“NE is also involved in regulating attention [86], in particular those related to emotional and neutral emotions [87], and this signalling network has been found altered in different brain areas in patients with ADHD [88].”

What the sources say

• Supported

  Citation [86] is attached only to the claim that NE is involved in regulating attention. The Introduction states that NE is strongly implicated in attentional processes, and the Discussion reports positive associations between noradrenergic responsiveness and attention. The emotional-versus-neutral and ADHD claims carry separate citations and are not attributed to this source. (LLM, conf=0.94)

  cites [86] Dahl MJ, Mather M, Sander MC, Werkle-Bergner M. Noradrenergic responsiveness supports selective attention across the adult lifespan. J Neurosci. 2020;40(22):4372–90. source
• Supported

  Citation [87] is attached to the claim about attention to emotional and neutral stimuli, not the separate ADHD claim attributed to [88]. The Results report that propranolol impaired detection of both emotional and neutral targets, while reboxetine improved detection of emotional targets but not neutral ones. Our copy provides no page number for this passage. (LLM, conf=0.93)

  cites [87] De tino B, Strange BA, Dolan RJ. Noradrenergic neuromodulation of human attention for emotional and neutral stimuli. Psychopharmacology. 2008;197(1):127–36. source
• Supported

  Citation [88] is attached to the claim that the NE signalling network is altered in brain areas of patients with ADHD, not to the preceding claims about attention or emotion. The Discussion reports reduced norepinephrine transporter availability in attention-related regions of adults with ADHD, especially in the right hemisphere, compared with controls. (LLM, conf=0.92)

  cites [88] Ulke C, Rullmann M, Huang J, et al. Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: a (S,S)-O-[11C]methylreboxetine positron emission tomography study. Transl Psychiatry. 2019;9(1):301. source

In the paper

“Moreover, a deficit in melatonin levels has been found in adults and children with ADHD [117], and melatonin has been used as a treatment for children with sleep problems diagnosed with ADHD [118].”

What the sources say

• Supported

  This source is cited as [118] for the treatment claim; the melatonin-deficit claim has a separate citation, [117]. In “Sleep–ADHD management,” the paper reports improved sleep-onset latency and sleep duration in children with stimulant-treated ADHD after bedtime melatonin, supporting the claim that melatonin has been used to treat their sleep problems. (LLM, conf=0.93)

  cites [117] Spruyt K, Gozal D. Sleep disturbances in children with attention-deficit/hyperactivity disorder. Expert Rev Neurother. 2011;11(4):565–77. source
• Supported

  Citation [118] is attached to the claim that melatonin has been used to treat sleep problems in children with ADHD, not to the separate melatonin-deficit claim cited to [117]. The Discussion reports treating children with ADHD who developed sleep problems after methylphenidate with melatonin. (LLM, conf=0.94)

  cites [118] Masi G, Fantozzi P, Villafranca A, et al. Effects of melatonin in children with attention-deficit/hyperactivity disorder with sleep disorders after methylphenidate treatment. Neuropsychiatr Dis Treat. 2019;15:663–7. source

In the paper

“This dysfunction of the immunoregulation by Treg cells and imbalance in the Th1/Th2 response might be a crucial factor in the development of allergies in children with ADHD [110], or a factor relating Th2-mediated hypersensitivity to ADHD development [111, 112].”

What the sources say

• Partly supported

  The Discussion suggests a possible link between immune regulation and asthma in children with ADHD, but discusses Th17 differentiation, not Treg-cell dysfunction or a Th1/Th2 imbalance. It also says the mechanisms remain unclear and that the review does not establish causative pathways, so it does not support calling the proposed mechanism a crucial factor. (LLM, conf=0.78)

  cites [110] Miyazaki C, Koyama M, Ota E, et al. Allergic diseases in children with attention deficit hyperactivity disorder: a systematic review and meta-analysis. BMC Psychiatry. 2017;17(1):120. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract hypothesizes that hypersensitivity to environmental stimuli may contribute to ADHD in some children. It does not identify Treg dysfunction or a Th1/Th2 imbalance as the factor linking hypersensitivity to ADHD; searches for those terms found no matching passage in our copy. (LLM, conf=0.78)

  cites [111] Pelsser LM, Buitelaar JK, Savelkoul HF. ADHD as a (non) allergic hypersensitivity disorder: a hypothesis. Pediatr Allergy Immunol. 2009;20(2):107–12. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [112] Scahill L, de Graft-Johnson A. Food allergies, asthma, and attention deficit hyperactivity disorder. J Child Adolesc Psychiatr Nurs. 1997;10(2):36–40 (quiz 1–2). source

In the paper

“Serotonin dysfunction plays a mediator role in ADHD-related hyperactive and impulsive behaviours [91] inducing impaired control of impulses, violent behaviour, concentration and appetite [89].”

What the sources say

• Partly supported

  The citation [91] is attached to the first clause; the later list of effects is cited to [89]. The Background says serotonin dysfunction is correlated with impulsivity, a characteristic of ADHD, and the Discussion links reduced serotonin activity to impulsive behavior. Neither passage establishes a mediating role or specifically links serotonin dysfunction to ADHD-related hyperactivity. (LLM, conf=0.85)

  cites [91] Wang CH, Liu C, Cong EZ, et al. Association of tryptophan hydroxylase-2 polymorphisms with oppositional defiant disorder in a Chinese Han population. Behav Brain Funct. 2016;12(1):30. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [89] Kent L, Doerry U, Hardy E, et al. Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis. Mol Psychiatry. 2002;7(8):908–12. source

In the paper

“These impairments might be the result of neurodegeneration, neurogenesis problems, altered proliferation–differentiation balance, deficient neurotrophic factors and, thereby, loss of neuronal viability [92].”

What the sources say

• Supported

  Section 2, “Neurogenesis” (page unavailable), says that disrupted proliferation–differentiation balance has consequences for brain development. Section 8, “Selective cell death” (page unavailable), describes neuronal degeneration and links reduced BDNF activity to neuronal loss and survival, supporting the sentence’s hedged explanation. (LLM, conf=0.88)

  cites [92] Dark C, Homman-Ludiye J, Bryson-Richardson RJ. The role of ADHD associated genes in neurodevelopment. Dev Biol. 2018;438(2):69–83. source

In the paper

“Alteration of glutamate/GABA equilibrium has been related to a diminished capability to focus on demanding tasks [98] and to result in DA dysregulation, causing inhibition of defective pyramidal neurons and a decrease shift in excitation towards tasks regulated in the PFC [99, 100].”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [98] Hu Y, Chen X, Gu H, Yang Y. Resting-state glutamate and GABA concentrations predict task-induced deactivation in the default mode network. J Neurosci. 2013;33(47):18566–73. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [99] Arnsten AF. The emerging neurobiology of attention deficit hyperactivity disorder: the key role of the prefrontal association cortex. J Pediatr. 2009;154(5):I-S43. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [100] Gilbert DL, Ridel KR, Sallee FR, Zhang J, Lipps TD, Wassermann EM. Comparison of the inhibitory and excitatory effects of ADHD medications methylphenidate and atomoxetine on motor cortex. Neuropsychopharmacology. 2006;31(2):442–9. source

In the paper

“Pro-inflammatory cytokines such as tumour necrosis factor beta (TNFβ), interferon alpha (IFNα), interleukin-1 (IL-1), IL-5, and IL-16 are found upregulated, whereas the anti-inflammatory cytokines IL-4 and IL-13 are downregulated, resulting in an inflammatory process that causes neuronal damage and contributes to ADHD symptomatology [60].”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [60] Verlaet AA, Noriega DB, Hermans N, Savelkoul HF. Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry. 2014;23(7):519–29. sourceExperimental — accuracy not yet measured

In the paper

“This promotes an imbalance in pro-inflammatory T helper 1 cell (Th1)/anti-inflammatory T helper 2 cell (Th2) cytokine profile making a more pro-inflammatory environment in ADHD [60, 102], which can be related to a defective regulatory T cell (Treg) regulation.”

What the sources say

• ?Could not verify

  No passage from our indexed copy addresses the proposed link between low cortisol, a Th1/Th2 cytokine imbalance, and defective Treg regulation in ADHD. Searches for cortisol, Th1, Treg, and pro-inflammatory cytokines returned no substantive passage; the only returned text was bibliographic information with no section or page. (LLM, conf=0.70)

  cites [60] Verlaet AA, Noriega DB, Hermans N, Savelkoul HF. Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry. 2014;23(7):519–29. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [102] Ma L, Chen YH, Chen H, Liu YY, Wang YX. The function of hypothalamus-pituitary-adrenal axis in children with ADHD. Brain Res. 2011;12(1368):159–62. source

In the paper

“ADHD seems to present a morphogenesis dysregulation [92, 121], with a high number of neurophysiological difficulties caused by neuronal network dysfunctions in the brain.”

What the sources say

• Supported

  The citation follows the claim about morphogenesis dysregulation, not the later statement about neuronal network dysfunction. The Introduction describes macroanatomical changes in ADHD resulting from disrupted neurodevelopmental mechanisms, including altered brain-region volumes and delayed cortical thickening. (LLM, conf=0.88)

  cites [92] Dark C, Homman-Ludiye J, Bryson-Richardson RJ. The role of ADHD associated genes in neurodevelopment. Dev Biol. 2018;438(2):69–83. source
• ?Not checked — no full text of the sourcecites [121] Donev R, Thome J. Inflammation: good or bad for ADHD? Atten Defic Hyperact Disord. 2010;2(4):257–66. source

In the paper

“The HpA axis is a hormonal system that controls stress responses [106] and affects several hormonal behaviours [107, 108].”

What the sources say

• Supported

  The citation is attached to the statement that the HPA axis is a hormonal system involved in stress responses, not to the separate claim about hormonal behaviours. The Physiology of the HPA Axis section describes its activation as a major component of the stress response and explains the hormone pathway involved. (LLM, conf=0.93)

  cites [106] Stephens MA, Wand G. Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Res. 2012;34(4):468–83. source
• Supported

  The citation attached to this source supports the clause about stress responses, not the separately cited clause about hormonal behaviours. The 'Anatomy of the stress response' section identifies the HPA axis as the principal structures mediating the stress response, and 'The HPA axis' section describes its hormonal response to stress. (LLM, conf=0.92)

  cites [107] Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 2006;8(4):383–95. source
• Supported

  The citation immediately after “controls stress responses” is attached to that part of the sentence. In the Introduction’s “The HPA axis” section, the paper describes the HPA axis as part of the stress system and says environmental stress can activate it. The separate claim about hormonal behaviours carries different citations and is not assessed here. (LLM, conf=0.88)

  cites [108] Bao AM, Swaab DF. The human hypothalamus in mood disorders: the HPA axis in the center. IBRO Rep. 2019;6:45–53. source

In the paper

“In children with ADHD, irregular sleep cycles, troubled sleep initiation, reduced sleep effectiveness with greater wakefulness periods and increased nocturnal activity have been observed, among others [117].”

What the sources say

• Partly supported

  The sections on sleep initiation and maintaining sleep report sleep-onset insomnia, increased night-time awakenings, and higher nocturnal activity in children with ADHD. The sleep-duration section describes variable sleep–wake patterns, but calls reduced sleep efficiency an anticipated complaint rather than a consistently observed finding; the review also notes that objective sleep findings are inconsistent. Page numbers are not available in our copy. (LLM, conf=0.82)

  cites [117] Spruyt K, Gozal D. Sleep disturbances in children with attention-deficit/hyperactivity disorder. Expert Rev Neurother. 2011;11(4):565–77. sourceExperimental — accuracy not yet measured

In the paper

“In this sense, higher glutamate levels and reduced GABA levels have been observed in children with ADHD, which indicates a bias towards neuron excitation that might be implicated in hyperactivity induction, although without a firm conclusion [101].”

What the sources say

• Partly supported

  The Introduction reports decreased prefrontal GABA in children with ADHD and increased glutamatergic levels in a separate study. The Results and Discussion link glutamate-related genetic variation to hyperactivity/impulsivity, but the Discussion says the study cannot determine the direction of effects; it does not establish an excitatory bias or show that such a bias induces hyperactivity. (LLM, conf=0.84)

  cites [101] Naaijen J, Bralten J, Poelmans G, et al. Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism. Transl Psychiatry. 2017;7(1): e999. sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, HpA axis involvement in typical ADHD comorbidities has been reported [109].”

What the sources say

• Supported

  In the paper’s discussion of externalizing psychopathology, the author reports HPA-axis findings for oppositional defiant and conduct disorder. The paper also discusses HPA-axis associations with anxiety and depression and explicitly refers to anxiety and depression as possible ADHD comorbidities. These passages support the broad claim that HPA-axis involvement in typical ADHD comorbidities has been reported; page numbers were not supplied in our copy. (LLM, conf=0.88)

  cites [109] Buitelaar JK. The role of the HPA-axis in understanding psychopathology: cause, consequence, mediator, or moderator? Eur Child Adolesc Psychiatry. 2013;22(7):387–9. source

In the paper

“Glutamate signalling is the most common excitatory synapse NT [93] and deficiencies in this signalling has been associated with ADHD symptoms [94], although it is unknown whether ADHD is associated with differences in glutamate levels [95–97].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [93] Bruce A, Johnson A, Ian L, Tin R, Keith R, Peter W. Internal organization of the cell; channels and the electrical properties. In: Molecular biology of the cell. 4th ed. New York: Garland Science; 2002.
• ?Not checked — no full text of the sourcecites [94] Medin T, Jensen V, Skare O, Storm-Mathisen J, Hvalby O, Bergersen LH. Altered alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function and expression in hippocampus in a rat model of attention-deficit/hyperactivity disorder (ADHD). Behav Brain Res. 2019;15(360):209–15. source
• ?Not checked — no full text of the sourcecites [95] Puts NA, Ryan M, Oeltzschner G, Horska A, Edden RAE, Mahone EM. Reduced striatal GABA in unmedicated children with ADHD at 7T. Psychiatry Res Neuroimaging. 2020;30(301): 111082. source
• Supported

  The citation [95–97] is attached to the uncertainty about glutamate levels, not the preceding claims about glutamate signalling. In the Comment section (page unavailable), the paper notes that earlier ADHD studies found elevated Glx, while its own Results (page unavailable) found no significant Glx difference. It also cautions that Glx is not a straightforward measure of excitatory glutamate signalling, supporting the citing sentence’s uncertainty rather than a definite conclusion about glutamate levels. (LLM, conf=0.86)

  cites [96] Edden RA, Crocetti D, Zhu H, Gilbert DL, Mostofsky SH. Reduced GABA concentration in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2012;69(7):750–3. source
• Partly supported

  The Results section reports no statistically significant difference between untreated ADHD participants and controls in this small sample, supporting uncertainty about glutamate-related levels. But the Introduction and Discussion describe earlier studies reporting significant glutamatergic differences in ADHD. The paper therefore does not support an unqualified statement that it is unknown whether any such differences are associated with ADHD; citations [93] and [94] attach to the other clauses. (LLM, conf=0.78)

  cites [97] Hammerness P, Biederman J, Petty C, Henin A, Moore CM. Brain biochemical effects of methylphenidate treatment using proton magnetic spectroscopy in youth with attention-deficit hyperactivity disorder: a controlled pilot study. CNS Neurosci Ther. 2012;18(1):34–40. sourceExperimental — accuracy not yet measured

In the paper

“Neuroinflammation is hypothesized to affect brain growth and thereby raises the risk of neurodevelopmental disorders through pathways such as glial activation, increased oxidative stress, problems related to neuronal growth and impaired NT activity [60].”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [60] Verlaet AA, Noriega DB, Hermans N, Savelkoul HF. Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry. 2014;23(7):519–29. sourceExperimental — accuracy not yet measured

In the paper

“Also, it has been shown that ephrin stimulates excitatory synapses development [127–129] and is closely related to neurogenesis, plasticity and learning [93].”

What the sources say

• Partly supported

  The citation [93] is attached to the claim about neurogenesis, plasticity and learning; the separate citations [127–129] accompany the synapse-development claim. The Discussion states that ephrin-A2 regulates neurogenesis, but our copy does not establish a relationship with plasticity or learning. (LLM, conf=0.88)

  cites [127] Homman-Ludiye J, Kwan WC, de Souza MJ, Rodger J, Bourne JA. Ephrin-A2 regulates excitatory neuron differentiation and interneuron migration in the developing neocortex. Sci Rep. 2017;7(1):11813. sourceExperimental — accuracy not yet measured
• Partly supported

  The source is cited for the first clause, not the neurogenesis, plasticity, and learning clause, which has a separate citation. Its Introduction and Discussion support a role for ephrin-B3 in regulating excitatory synapse density during development, but the Introduction explicitly says it is not required for synapse formation; it controls the local distribution of synapses instead. Thus, saying broadly that ephrin stimulates synapse development overstates the finding. (LLM, conf=0.83)

  cites [128] Henderson NT, Le chand SJ, Hruska M, Hippenmeyer S, Luo L, Dalva MB. Ephrin-B3 controls excitatory synapse density through cell-cell competition for EphBs. Elife. 2019;21:8. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [129] Calo L, Cinque C, Patane M, et al. Interaction between ephrins/Eph receptors and excitatory amino acid receptors: possible relevance in the regulation of synaptic plasticity and in the pathophysiology of neuronal degeneration. J Neurochem. 2006;98(1):1–10. source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [93] Bruce A, Johnson A, Ian L, Tin R, Keith R, Peter W. Internal organization of the cell; channels and the electrical properties. In: Molecular biology of the cell. 4th ed. New York: Garland Science; 2002.

In the paper

“Interestingly, canonical inflammation mediators, such as interleukin-1 beta (IL-1B) and TNF are induced in MPH treatment, suggesting a potential immunomodulatory role for the drug, although the evidence does not readily support it.”

What the sources say

• ?Could not verify

  The Discussion describes stimulant treatment in relation to oxidative stress, but does not address whether methylphenidate induces IL-1B or TNF or has an immunomodulatory role. Searches for those mediators and for inflammatory cytokines induced by methylphenidate found no passage addressing the claim. (LLM, conf=0.75)

  cites [125] Joseph N, Zhang-James Y, Perl A, Faraone SV. Oxidative stress and ADHD: a meta-analysis. J Atten Disord. 2015;19(11):915–24. sourceExperimental — accuracy not yet measured

In the paper

“LDX is the first stimulant prodrug indicated and recommended by guidelines in children at least 6 years of age when the MPH treatment is not optimal [132, 150], and also as first-line treatment in adults [133, 151] and for binge eating disorder [40] in the USA.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [132] National Institute for Health and Care Excellence. Attention deficit hyperactivity disorder: diagnosis and management. https://www.nice.org.uk/guidance/NG87. NICE guideline NG87. 2018.
• ?Not checked — no full text of the sourcecites [150] Frampton JE. Lisdexamfetamine dimesylate: a review in paediatric ADHD. Drugs. 2018;78(10):1025–36. source
• Supported

  The citation to this paper is attached to the adult first-line treatment claim, not the child or binge-eating indications. Section 7.4.1 (p. 9) identifies LDX as a formulation of dexamphetamine and reports amphetamines as the first pharmacological choice for adults with ADHD. (LLM, conf=0.87)

  cites [133] Kooij JJS, Bijlenga D, Salerno L, et al. Updated European consensus statement on diagnosis and treatment of adult ADHD. Eur Psychiatry. 2019;56:14–34. source
• ?Not checked — no full text of the sourcecites [151] Frampton JE. Lisdexamfetamine: a review in ADHD in adults. CNS Drugs. 2016;30(4):343–54. source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [40] VYVANSE® (lisdexamfetamine dimesylate) capsules, for oral use, CII. VYVANSE ® (lisdexamfetamine dimesylate) chewable tablets, for oral use, CII. Initial U.S. Approval: 20. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208510lbl.pdf.

In the paper

“Alterations in glutamate receptors (GRM-1, GRM-5, GRM-7 and GRM-8) have been associated with ADHD [124].”

What the sources say

• Supported

  The paper’s Abstract reports that copy-number variants affecting metabotropic glutamate receptor genes were enriched in ADHD cases and specifically identifies GRM1, GRM5, GRM7 and GRM8. It describes deletions in GRM5, GRM7 and GRM8 and duplications in GRM1, supporting the claimed association. (LLM, conf=0.94)

  cites [124] Elia J, Glessner JT, Wang K, et al. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet. 2011;44(1):78–84. source

In the paper

“Moreover, it has been suggested that ephrin family members have a role in ADHD-related synaptogenesis alterations [92, 130].”

What the sources say

• Partly supported

  Section 5, “Synaptogenesis” (page unavailable), identifies ephrin type-B receptor 2 (EPHB2) as a surface protein involved in stabilising synaptic contacts. It also discusses possible synaptic-density alterations in ADHD, but does not specifically link ephrin family members to ADHD-related alterations. (LLM, conf=0.82)

  cites [92] Dark C, Homman-Ludiye J, Bryson-Richardson RJ. The role of ADHD associated genes in neurodevelopment. Dev Biol. 2018;438(2):69–83. sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) suggests that loss of ephrin-A5 may contribute to ADHD-like behavioral phenotypes through neurodevelopmental alterations, citing its role in neurite outgrowth and axon targeting. It does not specifically identify ADHD-related alterations in synaptogenesis; that part of the claim is unsupported by our copy. (LLM, conf=0.84)

  cites [130] Sheleg M, Yochum CL, Wagner GC, Zhou R, Richardson JR. Ephrin-A5 deficiency alters sensorimotor and monoaminergic development. Behav Brain Res. 2013;236(1):139–47. sourceExperimental — accuracy not yet measured

In the paper

“Glutamate and some of its receptors are also involved in neurogenesis and proliferation [92].”

What the sources say

• Supported

  Section 2, “Neurogenesis,” describes glutamate as a positive regulator of neurogenesis and says that metabotropic glutamate receptors play roles in that process. It also reports that GRM5 activation increases expression of a factor that induces neural proliferation, while GRM7 knockdown increases proliferation. (LLM, conf=0.94)

  cites [92] Dark C, Homman-Ludiye J, Bryson-Richardson RJ. The role of ADHD associated genes in neurodevelopment. Dev Biol. 2018;438(2):69–83. source

In the paper

“It is the first-line pharmacological treatment recommended in current guidelines [132, 133] for children of at least 6 years of age and adults with ADHD.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [132] National Institute for Health and Care Excellence. Attention deficit hyperactivity disorder: diagnosis and management. https://www.nice.org.uk/guidance/NG87. NICE guideline NG87. 2018.
• Partly supported

  Section 7.4.1 (p. 9) says methylphenidate was among the stimulants recommended as first-line pharmacotherapy for adults in an earlier European consensus statement, and reports methylphenidate as the first pharmacological choice for children and adolescents. It does not specify a minimum age of 6, and the more recent evidence it discusses favors amphetamines, rather than methylphenidate, as the first choice for adults. (LLM, conf=0.88)

  cites [133] Kooij JJS, Bijlenga D, Salerno L, et al. Updated European consensus statement on diagnosis and treatment of adult ADHD. Eur Psychiatry. 2019;56:14–34. sourceExperimental — accuracy not yet measured

In the paper

“MPH is the most commonly prescribed medication to treat ADHD [134, 135].”

What the sources say

• Partly supported

  The Introduction states that MPH is the most commonly prescribed psychostimulant for patients with ADHD. The claim broadens that comparison to all medications, which this passage does not establish. (LLM, conf=0.88)

  cites [134] Pitzianti MB, Spiridigliozzi S, Bartolucci E, Esposito S, Pasini A. New insights on the effects of methylphenidate in attention deficit hyperactivity disorder. Front Psychiatry. 2020;11: 531092. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [135] Semrud-Clikeman M, Filipek PA, Biederman J, et al. Attention-deficit hyperactivity disorder: magnetic resonance imaging morphometric analysis of the corpus callosum. J Am Acad Child Adolesc Psychiatry. 1994;33(6):875–81. source

In the paper

“Neurotrophin-3 (NTF-3) has been also related to neuron survival [92].”

What the sources say

• ?Could not verify

  Section 8, “Selective cell death” (page not provided), links nerve growth factor and BDNF to neuronal survival, but does not identify neurotrophin-3 (NTF-3). Searches for “NTF-3 neurotrophin-3 neuron survival” and “NTF3 neuronal survival” found no passage in our copy addressing NTF-3’s role. (LLM, conf=0.72)

  cites [92] Dark C, Homman-Ludiye J, Bryson-Richardson RJ. The role of ADHD associated genes in neurodevelopment. Dev Biol. 2018;438(2):69–83. sourceExperimental — accuracy not yet measured

In the paper

“LDX inhibits the activity of two other important proteins, not shared with MPH, involved in the monoaminergic system described in ADHD: SERT [164] and MAO [165].”

What the sources say

• Partly supported

  The Pharmacology section says that d-amphetamine, the active metabolite of LDX, is a weak MAO inhibitor. The Pharmacodynamics section says LDX itself is inactive at enzymes in vitro, and the paper does not establish that MAO inhibition is absent with MPH. SERT is separately cited to [164] in the citing sentence, so it is not judged against this source. (LLM, conf=0.86)

  cites [164] Guerdjikova AI, Mori N, Casuto LS, McElroy SL. Novel pharmacologic treatment in acute binge eating disorder - role of lisdexamfetamine. Neuropsychiatr Dis Treat. 2016;12:833–41. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [165] Popovic B, Bhattacharya P, Sivaswamy L. Lisdexamfetamine: a prodrug for the treatment of attention-deficit/hyperactivity disorder. Am J Health Syst Pharm. 2009;66(22):2005–12. source

In the paper

“LDX is also a specific agonist of TAAR1 [169], a protein involved in DA pathway modulation [170].”

What the sources say

• Partly supported

  The Discussion and Conclusions section (page unavailable) says that amphetamine, the active metabolite of LDX, activates TAAR1 and suggests that LDX and TAAR1 agonism may work through similar mechanisms. It does not establish that LDX itself is a specific TAAR1 agonist. The separate dopamine-pathway clause is attached to citation [170], not this source. (LLM, conf=0.86)

  cites [169] Moore CF, Sabino V, Cottone P. Trace amine associated receptor 1 (TAAR1) modulation of food reward. Front Pharmacol. 2018;9:129. sourceExperimental — accuracy not yet measured
• Supported

  This source supports the clause attached to [170], which describes TAAR1 as involved in dopamine-pathway modulation. The “TAAR1 Knockout Mice” section discusses mechanisms by which TAAR1 may modulate dopaminergic neurotransmission. The claim that LDX is a specific agonist is attached to [169], not this source. (LLM, conf=0.93)

  cites [170] Sotnikova TD, Caron MG, Gainetdinov RR. Trace amine-associated receptors as emerging therapeutic targets. Mol Pharmacol. 2009;76(2):229–35. source

In the paper

“In PFC neurons, MPH indirectly activates the postsynaptic DRD1 and DRD5 [142] that uptake DA and transmit the signal in postsynaptic neurons [175].”

What the sources say

• Partly supported

  The Introduction says MPH indirectly activates D1 receptors in PFC neurons. It does not establish indirect activation of D5 receptors or identify D1 and D5 as postsynaptic receptors in this claim; the Results instead identify postsynaptic σ1 signaling in the NMDA-receptor response. The later statement about dopamine uptake carries a different citation and is not assessed here. (LLM, conf=0.87)

  cites [142] Zhang CL, Feng ZJ, Liu Y, et al. Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action. PLoS ONE. 2012;7(12): e51910. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [175] Gronier B. In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: involvement of dopamine D1 and alpha 2 adrenergic receptors. Eur Neuropsychopharmacol. 2011;21(2):192–204. source

In the paper

“MPH exerts its action promoting the downregulation of DA and NE transporter (DAT and NET) (protein targets) [139]. This leads to an increase of DA and NE levels in the prefrontal cortex (synaptic cleft) that control hyperactivity and deficits in inhibitory behaviour (improvement in attentional deficit and cognitive functioning) [139, 171].”

What the sources say

• Partly supported

  The Introduction states that MPH blocks DAT and NET, increasing extracellular dopamine and norepinephrine, and that low doses improve focused attention. It does not describe transporter downregulation. The Discussion says that, in non-human primates, increased dopamine was documented in the striatum and caudate, not the PFC; it also does not establish that the proposed PFC increase controls hyperactivity or inhibitory-behaviour deficits. (LLM, conf=0.88)

  cites [139] Rajala AZ, Populin LC, Jenison RL. Methylphenidate affects task-switching and neural signaling in non-human primates. Psychopharmacology. 2020;237(5):1533–43. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [171] Volkow ND, Fowler JS, Wang GJ, Ding YS, Gatley SJ. Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies. Eur Neuropsychopharmacol. 2002;12(6):557–66. source

In the paper

“Neuroinflammation is hypothesized to increase the risk of neurodevelopmental disorders and impaired NT activity [60].”

What the sources say

• ?Could not verify

  No eligible full-text passage in our copy addresses whether neuroinflammation increases the risk of neurodevelopmental disorders or impairs neurotransmitter activity. Searches for neuroinflammation, neurodevelopmental disorders, and neurotransmitters returned no matching full-text passage; the only substantive match was labeled Abstract, which cannot decide this verdict. (LLM, conf=0.68)

  cites [60] Verlaet AA, Noriega DB, Hermans N, Savelkoul HF. Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry. 2014;23(7):519–29. sourceExperimental — accuracy not yet measured

In the paper

“Recent evidence suggests the involvement of the immune system in several psychiatric conditions [203–205]; one of the most studied in this respect is depression [206–208].”

What the sources say

• Supported

  The citation is attached to the first clause, about immune involvement in several psychiatric conditions; the depression clause has separate citations. The Introduction states that increased pro-inflammatory cytokines occur not only in schizophrenia but also in other psychiatric disorders. No page number is available in our copy. (LLM, conf=0.90)

  cites [203] Muller N. Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations. Schizophr Bull. 2018;44(5):973–82. source
• Supported

  The Introduction (page unavailable) discusses immune dysregulation as a possible mechanism in schizophrenia, depression and bipolar disorder, and reports studies linking inflammatory markers to all three. This supports the immune-involvement clause; the separate claim that depression is among the most studied conditions carries different citations. (LLM, conf=0.91)

  cites [204] Perry BI, Upthegrove R, Kappelmann N, Jones PB, Burgess S, Khandaker GM. Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: a bi-directional two-sample mendelian randomization study. Brain Behav Immun. 2021;97:176–185. source
• Supported

  Section 2.1 (Inflammation Theory; page unavailable) says immune dysfunction and chronic inflammation have been implicated in numerous psychiatric disorders, then describes longstanding research linking immune activity to depression. Section 2.2 (Cytokines as Markers of Microglial Activation; page unavailable) reviews immune-marker studies in major depressive disorder and bipolar disorder, supporting the characterization of depression as a well-studied example. (LLM, conf=0.88)

  cites [205] Sakrajda K, Szczepankiewicz A. Inflammation-related changes in mood disorders and the immunomodulatory role of lithium. Int J Mol Sci. 2021;22(4):1532. source
• Partly supported

  The Introduction (page unavailable) describes extensive research linking immune dysfunction with major depressive disorder, including consistent reports of elevated proinflammatory cytokines. It does not compare depression with other psychiatric conditions, so it does not establish that depression is one of the most studied in this respect. (LLM, conf=0.78)

  cites [206] Alvarez-Mon MA, Gomez-Lahoz AM, Orozco A, et al. Blunted expansion of regulatory T lymphocytes is associated with increased bacterial translocation in patients with major depressive disorder. Front Psychiatry. 2020;11: 591962. sourceExperimental — accuracy not yet measured
• Supported

  The citation to this source is attached to the clause about depression, not the preceding claim about several psychiatric conditions. The Introduction describes accumulating clinical and preclinical evidence linking inflammation to depression and identifies that link as the review’s focus. (LLM, conf=0.93)

  cites [207] Sakamoto S, Zhu X, Hasegawa Y, et al. Inflamed brain: targeting immune changes and inflammation for treatment of depression. Psychiatry Clin Neurosci. 2021;75(10):304–11. source
• ?Not checked — no full text of the sourcecites [208] Troubat R, Barone P, Leman S, et al. Neuroinflammation and depression: a review. Eur J Neurosci. 2021;53(1):151–71. source

In the paper

“This PKC activation decreases DAT1 [181], NET1 [182] and SERT [183] cell surface expression, intensifying the direct blockage of monoamine transporters by LDX and improving the neurotransmission imbalance in ADHD.”

What the sources say

• ?Could not verify

  Citation [182] is attached to the claim that PKC activation decreases NET1 cell-surface expression. The Results passage describes cell-surface internalization of engineered dopamine D2 receptors, not NET1. Searches for PKC, NET1, and norepinephrine-transporter internalization found no passage addressing that claim; the downstream claims about LDX and ADHD are likewise not established by this copy. (LLM, conf=0.76)

  cites [181] Peterson SM, Pack TF, Wilkins AD, et al. Elucidation of G-protein and beta-arrestin functional selectivity at the dopamine D2 receptor. Proc Natl Acad Sci USA. 2015;112(22):7097–102. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [182] Bermingham DP, Blakely RD. Kinase-dependent regulation of monoamine neurotransmitter transporters. Pharmacol Rev. 2016;68(4):888–953. source
• ?Not checked — no full text of the sourcecites [183] Jayanthi LD, Samuvel DJ, Blakely RD, Ramamoorthy S. Evidence for biphasic effects of protein kinase C on serotonin transporter function, endocytosis, and phosphorylation. Mol Pharmacol. 2005;67(6):2077–87. source

In the paper

“Several studies have exposed that the long-term use of MPH induces the DA neuron loss and microglia activation causing an increase in pro-inflammatory markers TNFα and IL-1β, among others, resulting in the activation of neuroinflammation and triggering a neurodegenerative process [192, 193].”

What the sources say

• Partly supported

  The Discussion reports that chronic 10 mg/kg MPH caused a small but significant loss of dopamine neurons in mice, and the Results report increased activated microglia at that dose. But the Results found increased TNFα and IL-6 expression only after an acute dose; the Discussion explicitly says inflammatory gene expression did not increase after chronic administration. IL-1β was examined but is not reported as increased, and the proposed link between inflammation and neuronal loss is a hypothesis rather than an established causal chain. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [192] Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS ONE. 2012;7(3): e33693. sourceExperimental — accuracy not yet measured
• Partly supported

  The “Neurotoxicity profile of METH and MDMA” section reports long-lasting dopaminergic deficits and increases in TNF-α and IL-1β for methamphetamine (METH) and MDMA, not methylphenidate (MPH). The “Mechanisms of toxicity > Inflammation” section says microglial activation may contribute to neurotoxicity, but the role of these cytokines remains uncertain. The source therefore supports parts of the proposed pathway for different drugs, not the claim that long-term MPH use causes it. (LLM, conf=0.88)

  cites [193] Yamamoto BK, Raudensky J. The role of oxidative stress, metabolic compromise, and inflammation in neuronal injury produced by amphetamine-related drugs of abuse. J Neuroimmune Pharmacol. 2008;3(4):203–17. sourceExperimental — accuracy not yet measured

In the paper

“It has been assessed in ADHD comorbid disease, such as bipolar disorder in animal models [160], in which LDX increased the pro-inflammatory cytokines TNFα and IL-6, and also the anti-inflammatory cytokines IL-4 and IL-10 in the frontal cortex, striatum and serum [160, 198].”

What the sources say

• ?Not checked — no full text of the sourcecites [160] Valvassori SS, Resende WR, Varela RB, et al. The effects of histone deacetylase inhibition on the levels of cerebral cytokines in an animal model of mania induced by dextroamphetamine. Mol Neurobiol. 2018;55(2):1430–9. source
• ?Could not verify

  The Clinical Association Analyses section describes genotyping human subjects with bipolar disorder, schizophrenia, and matched controls. Our copy contains no passage addressing LDX treatment or its effects on TNFα, IL-6, IL-4, or IL-10 in animal models; searches for those terms and for inflammatory cytokines found none. (LLM, conf=0.76)

  cites [198] Pinsonneault JK, Han DD, Burdick KE, et al. Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology. 2011;36(8):1644–55. sourceExperimental — accuracy not yet measured

In the paper

“Several studies have shown that MPH modulates oxidative stress in the brain [223, 224], either increasing or reducing reactive oxygen species (ROS) depending on age, drug dose and brain region, and relate that to neural viability.”

What the sources say

• Supported

  The Results (section labeled Abstract; page unavailable) report increased superoxide in young rats after acute MPH treatment and decreased superoxide in adult rats after chronic treatment, with effects varying by dose and brain region. The discussion in the same section links oxidative species to neuronal toxicity and describes possible protection from oxidative insult; it does not report a direct measure of neural viability. (LLM, conf=0.89)

  cites [223] Gomes KM, Inacio CG, Valvassori SS, et al. Superoxide production after acute and chronic treatment with methylphenidate in young and adult rats. Neurosci Lett. 2009;465(1):95–8. source
• ?Not checked — no full text of the sourcecites [224] tins MR, Reinke A, Petronilho FC, Gomes KM, Dal-Pizzol F, Quevedo J. Methylphenidate treatment induces oxidative stress in young rat brain. Brain Res. 2006;1078(1):189–97. source

In the paper

“This mechanism observed with the use of amphetamines leads to neurodegeneration and lower cell survival [216].”

What the sources say

• ?Could not verify

  The Results and Discussion address ethanol exposure in the developing cerebellum, not amphetamine use. The Discussion mentions apoptosis after high-dose ethanol exposure but does not establish that the proposed CBP mechanism causes neurodegeneration or reduced cell survival. Searches for amphetamines and for the claimed survival outcome found no passage addressing the claim. (LLM, conf=0.76)

  cites [216] Guo W, Crossey EL, Zhang L, et al. Alcohol exposure decreases CREB binding protein expression and histone acetylation in the developing cerebellum. PLoS ONE. 2011;6(5):e19351. sourceExperimental — accuracy not yet measured

In the paper

“LDX increases the thiobarbituric acid-reactive substances in the cerebellum, hippocampus and cerebral cortex, although its MoA is unknown [225].”

What the sources say

• Partly supported

  The TBARS section reports that repeated LDX exposure increased TBARS in the cerebellum, hippocampus and cerebral cortex of rats. The discussion says the mechanisms responsible for LDX-induced oxidative stress have not been fully identified, but suggests dopamine metabolism and oxidation as a possible mechanism. Calling LDX’s mode of action simply “unknown” overstates that qualification. (LLM, conf=0.85)

  cites [225] Eger GA, Ferreira VV, Batista CR, et al. Antioxidant effect of simvastatin throught oxidative imbalance caused by lisdexamfetamine dimesylate. An Acad Bras Cienc. 2016;88(1):335–48. sourceExperimental — accuracy not yet measured

In the paper

“LDX promotes the activation of pro-inflammatory cytokines such as TNFα and IL-6, although it also promotes the expression of the anti-inflammatory cytokines IL-4 and IL-10 in the frontal cortex, striatum and serum.”

What the sources say

• ?Not checked — no full text of the sourcecites [160] Valvassori SS, Resende WR, Varela RB, et al. The effects of histone deacetylase inhibition on the levels of cerebral cytokines in an animal model of mania induced by dextroamphetamine. Mol Neurobiol. 2018;55(2):1430–9. source
• ?Could not verify

  The 3′ UTR reporter-assay and Clinical Association Analyses passages concern dopamine transporter gene variants, not LDX or cytokine expression. Searches for LDX, TNFα, IL-6, IL-4, IL-10, and inflammatory cytokines found no passage in our copy addressing the claim; page numbers were not available. (LLM, conf=0.78)

  cites [198] Pinsonneault JK, Han DD, Burdick KE, et al. Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology. 2011;36(8):1644–55. sourceExperimental — accuracy not yet measured

In the paper

“ADHD pathophysiology is largely unknown.”

• Also stated in: § Abstract · hedged

  “The aetiology and pathophysiology of ADHD are incompletely understood; both genetic and environmental factors have been associated with the disorder and its grade of burden, and also the relationship between the molecular mechanisms of pharmacological treatments and their clinical implications.”

In the paper

“There are several causative cellular and molecular processes related to the ADHD development, among which NT imbalances or alterations in neuronal plasticity and neuronal survival are very well described.”

In the paper

“Nevertheless, other less studied processes are gaining relevance as regards their involvement in ADHD, such as the role of neuroinflammation and alteration of circadian rhythms.”

In the paper

“Few published studies evaluating molecular data on the mechanism of action (MoA) of MPH and LDX on ADHD are available and most of them are based on animal models.”

In the paper

“and also the relationship between the molecular mechanisms of pharmacological treatments and their clinical implications.”

In the paper

“In addition, we performed handsearching of reference lists in the articles identified through the structured searches.”

In the paper

“While it is not a formal systematic review, we applied structured search strategies covering PubMed/MEDLINE database.”

In the paper

“Nonstimulants are considered as second-line medication and are administered when stimulants are contraindicated or because of lack of response or intolerance [35].”

What the sources say

• ?Not checked — no full text of the sourcecites [35] Caye A, Swanson JM, Coghill D, Rohde LA. Treatment strategies for ADHD: an evidence-based guide to select optimal treatment. Mol Psychiatry. 2019;24(3):390–408. source

In the paper

“It is presumed that is likely related to a blockage of the reuptake of NE and DA into the presynaptic neuron and an increase in the release of these monoamines into the extraneuronal space [39].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [39] Ficha Tecnica Elvanse 30 mg capsulas duras. https://cima.aemps.es/cima/dochtml/ft/77642/FT_77642.html.

In the paper

“Pharmacologic treatment is based on stimulants [amphetamines, such as the prodrug lisdexamfetamine dimesylate (LDX), and methylphenidate (MPH)] and nonstimulants (atomoxetine, guanfacine, clonidine, bupropion, modafinil) [17].”

What the sources say

• ?Not checked — no full text of the sourcecites [17] Cortese S. Pharmacologic treatment of attention deficit-hyperactivity disorder. N Engl J Med. 2020;383(11):1050–6. source

In the paper

“Moreover, a nocebo effect affecting patient tolerability is reported, and it is mainly translated into dropouts due to adverse events or any other reason, and weight loss [37]”

What the sources say

• ?Not checked — no full text of the sourcecites [37] Faraone SV, Newcorn JH, Cipriani A, et al. Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis. Mol Psychiatry. 2022;27(1):212–9. source

In the paper

“In fact, intellectual disability appears before ADHD and it might condition the presence of ADHD.”

In the paper

“The estimated involvement of environmental factors in ADHD pathogenesis is around 20–30% [64]”

What the sources say

• ?Not checked — no full text of the sourcecites [64] Wallis D, Russell HF, Muenke M. Review: genetics of attention deficit/hyperactivity disorder. J Pediatr Psychol. 2008;33(10):1085–99. source

In the paper

“A wide variety of other neurodevelopmental disorders and cognitive and behavioural problems have been found in ADHD: dyslexia, reasoning disorder, dyscalculia, written language expression disorder, language difficulties, motor control difficulties and also autism spectrum disorders [72].”

What the sources say

• ?Not checked — no full text of the sourcecites [72] Wu J, Xiao H, Sun H, Zou L, Zhu LQ. Role of dopamine receptors in ADHD: a systematic meta-analysis. Mol Neurobiol. 2012;45(3):605–20. source

In the paper

“DA interacts with five different receptors localized in postsynaptic neurons [75], which are dysregulated in several brain regions of patients with ADHD.”

What the sources say

• ?Not checked — no full text of the sourcecites [75] Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother. 2014;48(2):209–25. source

In the paper

“However, ADHD-associated mutations have been reported to include a wide range of different physiological processes including circadian rhythm mechanisms [63].”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Bijlenga D, Vollebregt MA, Kooij JJS, Arns M. The role of the circadian system in the etiology and pathophysiology of ADHD: time to redefine ADHD? Atten Defic Hyperact Disord. 2019;11(1):5–19. source

In the paper

“Neuronal network morphogenesis is based on an effective equilibrium between neuroplasticity and neurodegeneration, as well as the formation of new cells through proliferation/survival signalling and cytoskeletal structures [120].”

What the sources say

• ?Not checked — no full text of the sourcecites [120] Lewis TL Jr, Polleux F. Neuronal morphogenesis: Golgi outposts, acentrosomal microtubule nucleation, and dendritic branching. Neuron. 2012;76(5):862–4. source

In the paper

“In this sense, the dopaminergic DA receptor 4 (DRD4) gene is strongly involved in translating light into electrical signals in the retina, and there is a strong circadian pattern in its transcription [63].”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Bijlenga D, Vollebregt MA, Kooij JJS, Arns M. The role of the circadian system in the etiology and pathophysiology of ADHD: time to redefine ADHD? Atten Defic Hyperact Disord. 2019;11(1):5–19. source

In the paper

“Although delayed sleep-phase is not enough to developed ADHD symptoms, it has been reported that treatments for sleep problems have promoted a reduction of ADHD symptoms [63].”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Bijlenga D, Vollebregt MA, Kooij JJS, Arns M. The role of the circadian system in the etiology and pathophysiology of ADHD: time to redefine ADHD? Atten Defic Hyperact Disord. 2019;11(1):5–19. source

In the paper

“Moreover, serotonin regulates DA activity through its receptors 5-hydroxytryptamine receptor 1B (5-HTR1B) or 5-hydroxytryptamine receptor 2A (5-HTR2A). The dysfunction of these receptors can lead to problems of serotonin–DA dynamics, resulting in ADHD symptoms [89, 90].”

What the sources say

• ?Not checked — no full text of the sourcecites [89] Kent L, Doerry U, Hardy E, et al. Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis. Mol Psychiatry. 2002;7(8):908–12. source
• ?Not checked — no full text of the sourcecites [90] Hawi Z, Dring M, Kirley A, et al. Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample. Mol Psychiatry. 2002;7(7):718–25. source

In the paper

“Sleep disturbances and deficit of alertness have also been found to be linked to abnormal eating behaviours, including binge eating, which is a common ADHD comorbidity; this link is hypothesized to involve the hypocretin/orexin system through hypoactivation of hypocretin/orexin neurons from perifornical and dorsomedial hypothalamic neurons (involved in arousal) and overactivation of hypocretin/ore”

What the sources say

• ?Not checked — no full text of the sourcecites [119] Cortese S, Konofal E, Lecendreux M. Alertness and feeding behaviors in ADHD: does the hypocretin/orexin system play a role? Med Hypotheses. 2008;71(5):770–5. source

In the paper

“Mutations in CLOCK gene have been associated with ADHD, indicating that the disrupted circadian pathways could exacerbate the symptoms of this disease [113], including ADHD-associated aggressiveness symptoms [115].”

What the sources say

• ?Not checked — no full text of the sourcecites [113] Lee YA, Goto Y. Habenula and ADHD: convergence on time. Neurosci Biobehav Rev. 2013;37(8):1801–9. source
• ?Not checked — no full text of the sourcecites [115] Mogavero F, Jager A, Glennon JC. Clock genes, ADHD and aggression. Neurosci Biobehav Rev. 2018;91:51–68. source

In the paper

“Moreover, the circadian system regulates dopaminergic system and therefore DA production is subjected to circadian rhythm variations [113].”

What the sources say

• ?Not checked — no full text of the sourcecites [113] Lee YA, Goto Y. Habenula and ADHD: convergence on time. Neurosci Biobehav Rev. 2013;37(8):1801–9. source

In the paper

“ADHD also involves a delayed sleep-phase symptom (sleep disturbances) typical of sleep onset insomnia [116] and other behavioural symptoms related to ADHD [63].”

What the sources say

• ?Not checked — no full text of the sourcecites [116] Corkum P, Tannock R, Moldofsky H. Sleep disturbances in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1998;37(6):637–46. source
• ?Not checked — no full text of the sourcecites [63] Bijlenga D, Vollebregt MA, Kooij JJS, Arns M. The role of the circadian system in the etiology and pathophysiology of ADHD: time to redefine ADHD? Atten Defic Hyperact Disord. 2019;11(1):5–19. source

In the paper

“One such protein involved is BDNF, which stimulates neuronal development and maintenance, regulates NT function and contributes in neuronal plasticity processes, such as long-term potentiation and learning [122].”

What the sources say

• ?Not checked — no full text of the sourcecites [122] Shim SH, Hwangbo Y, Kwon YJ, et al. Increased levels of plasma brain-derived neurotrophic factor (BDNF) in children with attention deficit-hyperactivity disorder (ADHD). Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1824–8. source