[144] ADHD in adults

[144] ADHD in adults

Vignette: Your 23-year-old male primary care patient went to a walk-in clinic after watching a TikTok video about ADHD. He was referred to a family physician with a special interest in ADHD. Now in your office, he presents a letter recommending treatment with lisdexamfetamine (Vyvanse) – mainly on the basis of his score on the Adult ADHD Self-Report Scale. Although you did not request this opinion, your patient would like you to prescribe medication. You are aware of intense promotion for Vyvanse.1,2 How should you respond?

Summary and Conclusions

  • Overdiagnosis of adult ADHD and promotion of drug treatments are driving a concerning prescribing epidemic for stimulant drugs and atomoxetine.
  • Reliable diagnosis is complex and requires documentation of childhood symptoms. ADHD rating scales cannot substitute for detailed clinical assessment.
  • Evidence from randomized controlled trials about drug efficacy and safety is derived mostly from industry-funded studies lasting ≤ 12 weeks that measured subjective symptom scales. We know little about important functional outcomes such as social and employment success and overall health.
  • Amphetamines and methylphenidate do not enhance or normalize ability to learn or apply knowledge in everyday life.
  • Many adults experience adverse effects from ADHD medications. Stimulants can induce pharmacological tolerance, dependence, and problems with withdrawal and misuse.
  • If you prescribe for adult ADHD, monitor patients within 1-2 weeks for initial assessment of safety, and improvement in functions important to success in family life and work. Then reassess regularly.
  • Lisdexamfetamine (Vyvanse) is substantially more expensive than other stimulants, but has no proven advantage.

Attention deficit hyperactivity disorder (ADHD) is a cognitive and behavioural neurodevelopmental condition, originally recognized and treated only in children. It is a highly heritable but heterogeneous phenotype, rather than a categorical distinction of “disorder” versus “health.”3 As for all psychiatric conditions, no simple diagnostic test is available. Competent diagnosis requires a comprehensive family, gestational, and developmental history, and observation over time. To diagnose adult ADHD, documented symptoms must have occurred during childhood. While questionnaires are necessary and psychometric tests are ancillary, alone they are insufficient bases for valid diagnosis.

Since 2008, the Therapeutics Initiative has released three Therapeutics Letters and a drug assessment on ADHD pharmacotherapy for children and adolescents.4-7 In 2012, we highlighted the rising trend of ADHD diagnoses in younger children starting primary school.8 This Letter examines evidence on adult ADHD, with an emphasis on drug treatments.

Although most evidence is short-term and of questionable quality, it surpasses what is available for alternatives like cognitive behavioural therapy. We find that challenges in diagnosis and limited long-term evidence continue to hinder evidence-based decision-making and patient safety.

A July 2023 multidisciplinary webinar available with open access from the British Medical Journal explores what we know and do not know about ADHD and its treatment.9 Presentations cover challenges in appropriate medical diagnosis and treatment, including the weak precision of diagnostic scales and rapidly increasing non-clinical “diagnosis” via social media – especially TikTok.

Overdiagnosis and overtreatment in children

Increasing medication of children and suspected overdiagnosis was first reported from the USA in 1999, but is now well recognized.10-13 In British Columbia, we demonstrated in 2012 a potent birth-month effect for diagnosis and treatment of pediatric ADHD.8 Compared with children born in January (earlier in a calendar year) boys born from September through December were 41% more likely, and girls 77% more likely to be prescribed a stimulant. Related to age at first school entry, Quebec investigators term this phenomenon the “medicalization of immaturity.”14 Also reported in France and the United States,15,16 it was confirmed from 12 countries by a 2019 systematic review that noted only a weak relative age effect in Denmark, where school entry is often delayed for relatively young children.17 During the Covid-19 pandemic, reported ADHD symptoms increased in children.18

This relative age effect can result in a life-long diagnosis of a mental disorder attributable solely to age, rather than true illness. A Dutch analysis of methylphenidate prescriptions from 1995-2015 concluded that dramatically increased incidence was not related to new evidence, and that starting doses often exceeded Dutch guidelines.19

How common is adult ADHD?

In children diagnosed with ADHD, some symptoms are known to persist for up to 16 years into young adulthood.20 Estimates of persistence vary widely from 4 to 77%, depending on the assessment method.21 In 2022, Canadian adult prevalence was estimated at 2.9%.22

By 2010, adult ADHD drug treatment rates ranged from 0.03%-0.5% in western Europe, Asia and Australia, but reached 1.42% in North America.23 A Lancet Psychiatry editorial highlighted frequent overdiagnosis and stimulant overuse in wealthy countries, but also noted potential under-treatment.24 Prescriptions for Canadian adults, primarily methylphenidate and amphetamines, quadrupled between 2005 and 2015, especially among young adult males.25

From 2015 to 2019, ADHD drug sales data from 64 countries showed a 10% yearly increase in per capita consumption; in Canada the annual increase was over 11%.26 About one in nine children and adolescents in Canada and the USA used ADHD medication, mostly methylphenidate and amphetamines, far higher than in other countries. If this trend persists, adult stimulant treatment rates will also increase.

Our analysis of utilization data (Figure) shows a dramatic increase in adult ADHD medication use in British Columbia from 2004 through 2022. Data are for prescription drugs with a Health Canada indication for treatment of adult ADHD, dispensed to BC residents aged 18+ with a diagnosis code for ADHD in the prior 10 years. Total ADHD medication use in adults has increased at an annual compounded rate of 17% since 2004, from 1 user per 1000 adult population in 2004 to 16.5 users per 1000 adult population in 2022. Combined public and private expenditures for these medications in British Columbia reached a total of $46.5 million in 2022.

How reliable is diagnosis?

Current diagnosis of ADHD depends partly on subjective rating scales and questionnaires that are subject to cognitive bias. Questionnaires can result in false “diagnoses,” especially when the questions reflect typical daily human experiences and challenges, or reported symptoms overlap with other conditions like anxiety or major depression or different learning disabilities.21,24,27 Self-scoring tools cannot substitute for careful clinical diagnosis based on comprehensive history and observation in multiple contexts including home, school, and work. Establishing the presence of characteristic symptoms by age 12 may require a search for documentation such as old school report cards, or at least completion of a retrospective rating scale by people who knew the patient during childhood.

The Adult ADHD Self-Report Scale (ASRS-V1.1) is a symptom checklist consisting of the 18 DSM-IV-TR criteria, considered valid for congruence between self-rating and clinician-rating and recommended by the Canadian ADHD Resource Alliance (CADDRA) Guidelines 2021.28 Toronto’s Centre for Addiction and Mental Health (CAMH) recommends the American Psychiatric Association’s Diagnostic and Statistical Manual V (DSM-V) criteria for adult ADHD diagnosis29 and the Weiss Functional Impairment Rating Scale (WFIRS) which has been validated psychometrically.30

ADHD symptom rating scales may be useful to suggest a detailed clinical assessment. But patients and practitioners should not confuse them with diagnostic tools, especially because ADHD does not require urgent diagnosis. Like CADDRA Guidelines, a “This Changed My Practice” article by an experienced British Columbia psychiatrist suggests that a positive screen warrants 3-4 follow-up visits before diagnosis.31

Overlap between ADHD and substance use disorders is well recognized.28 For successful treatment and to avoid creating new problems, it is crucial to evaluate for alcohol, cannabis, opioid, stimulant and other substance use disorders before prescribing medication with potential for misuse.

Pharmacotherapy with stimulants and atomoxetine

Most adults treated for ADHD receive amphetamines or methylphenidate; far fewer take atomoxetine (Figure). This Letter does not discuss guanfacine or bupropion, which are not approved in Canada for adult ADHD. Amphetamines and methylphenidate enhance the central norepinephrine and dopamine systems and can induce pharmacological tolerance and dependence during long-term use. Product monographs include black box warnings about the potential requirement for increasing doses, physical and psychological dependence, and possible misuse, including “diversion” for non-medical use as “recreational” or “performance enhancing” drugs.32-34 The home page of Vyvanse drug manufacturer Takeda’s US promotional website shows this prominently, stating: “Vyvanse has a high chance for abuse and may cause physical and psychological dependence. Your healthcare provider should check you for signs of abuse and dependence before and during treatment.”2 Compared with stimulants, the selective norepinephrine uptake inhibitor atomoxetine is believed to have a lower risk of diversion, but also increases blood pressure and heart rate, and more frequently causes anorexia, nausea, vomiting or somnolence.35 The manufacturer warns about the potential for suicidal thinking or attempts.36

Harms demonstrated in clinical trials that are significantly more common with methylphenidate than with placebo, but similar to amphetamines, include appetite suppression, dry mouth, headache, palpitations, insomnia, sexual dysfunction, anxiety, feeling jittery, irritable or agitated, and aggression.37 Apart from sudden cardiac death, acute psychosis may be the most serious potential complication. United Kingdom drug regulators noted an increased reporting of “psychosis/mania” in 3 trials of methylphenidate vs placebo (methylphenidate 3% vs placebo 1%).37 In a large database study of people ages 13-25 treated with prescription stimulants in the US between 2014-2015, new psychosis was estimated to affect about 1 in 660 patients. Amphetamine prescriptions appeared more likely than methylphenidate to precede a new diagnostic code for psychosis (HR 1.64; 95% CI 1.31 to 2.09).38 This type of evidence does not establish causation, and the psychosis is usually self-limited.39 However, a new study of the World Health Organization pharmacovigilance database also raises concern about stimulant-induced psychotic delusions.40 Misuse of stimulants for sports performance can cause seizures, myocardial infarction, cardiomyopathy, and even sudden death.41

BC’s Provincial Academic Detailing Service summarized pharmacology, formulations and clinical considerations for drugs licensed for ADHD inCanada.35 A table of interactions illustrates potential pharmacokinetic and pharmacodynamic issues.

Why treat adult ADHD?

Treatment goals should focus on reasonable expectations for functional improvement and quality of life. For example, improved academic and work performance, stable employment, interpersonal relationships, and overall health outrank the surrogate outcome of rating scale scores. Prescribing decisions should involve informed patient consent, including a clear understanding of potential harms and the paucity of evidence about long-term effects. Patients should appreciate, as for other drugs affecting the brain, that stimulant dependence and withdrawal symptoms are possible.32-34,42,43

Amphetamines and methylphenidate do not enhance or normalize ability to learn or apply knowledge in everyday life. They do not improve – but may impair – short-term acquisition of information and “cognitive flexibility” in adults with ADHD compared with control subjects.44,45 For example, in a complex simulation problem intended to mimic tasks of daily life (optimizing the value of items placed in a knapsack) stimulants increased efforts made by volunteers aged 18 to 35 (N=40), but significantly decreased the quality of results.46 The 2022 systematic review of extended-release methylphenidate summarizes some uncertainties about its cognitive effects.37

Evidence for pharmacotherapy from short-term RCTs in adults

Evidence about drug therapy in children and adolescents remains controversial. For example, a recent unconflicted review of systematic reviews (SRs) and meta-analyses (MAs) concluded that “the evidence claiming that methylphenidate is beneficial in treating children and adolescents with ADHD was of very low certainty.”47 The uncertainty of evidence is reflected in the absence of stimulants from the World Health Organization’s 2023 Model Lists of Essential Medicines for Children or Adults.48 WHO twice rejected an application to include methylphenidate, most recently after review in 2021.49

Evidence for pharmacotherapy of adult ADHD is derived almost exclusively from randomized controlled trials (RCTs) lasting ≤ 12 weeks. Most systematic reviews and meta-analyses (SR/MAs) conclude that evidence for efficacy and safety from short-term treatment is weak, and limited mostly to rating scale scores. They all conclude that we know very little about long-term drug treatment. Meta-analytic results from different measurement scales are often reported as standardized mean differences (SMD, Cohen’s d), which cannot be translated into a likelihood or magnitude of success for clinically important functional outcomes.

A 2022 Cochrane SR/MA of methylphenidate extended-release (ER) formulations that includes unpublished information identified 24 relevant RCTs (N=5,066, median age 36, median treatment duration 8 weeks).37 Most trials excluded people with psychiatric co-morbidity; 90% of participants were enrolled in industry-funded trials. A single trial (N=419) followed patients for 52 weeks, and 2 short trials (N=314) used active comparators (atomoxetine, bupropion). The Cochrane reviewers assessed evidence as “very low-certainty” for “small-to-moderate” effects of methylphenidate vs. placebo for ADHD symptoms rated by participants, investigators, and family. There was no effect on days missed from work. Methylphenidate increased the risk for all adverse effects (RR 1.27, 95% CI 1.19 to 1.37) and increased the point estimate for serious adverse events (RR 1.43, 95% CI 0.85 to 2.43). A 2021 Cochrane SR/ MA of immediate-release (IR) methylphenidate vs placebo identified 10 RCTs, N=497 adults. The authors concluded there was at best “very low-certainty evidence” for improvements on rating scales.50

In 2020, Canadian reviewers published a SR and network MA (SR/NMA) of any drug treatment of adult ADHD. This included 81 RCTs, mostly industry funded, total N=12,423.51 Trial durations were 2-52 weeks, mostly of methylphenidate (36 RCTs), amphetamines (21 RCTs), and atomoxetine (20 RCTs). Reviewers assessed only 5 of 81 RCTs as at low risk of bias, and ¾ of the RCTs lasted < 12 weeks. Many participants had previously received prescription stimulants. From trials lasting > 12 weeks, the reviewers assessed clinical scale responses and (when reported) functional outcomes, including quality of life, executive function, driving behaviour, and a broad range of safety outcomes. Differences in symptom scores were small, subject to bias from treatment unblinding, and when limited to studies at low risk of bias, the authors found “no significant difference between ADHD pharmacotherapy and placebo.” They considered certainty of evidence for all outcomes “very low to low.” No trial > 12 weeks assessed executive function.

A 2018 Cochrane SR/MA of dexamphetamine, lisdexamfetamine, and mixed amphetamine salts for adult ADHD identified 19 RCTs (N=2,521, mean age 35, mean duration 5.3 weeks).52 Only 3/19 RCTs exceeded 8 weeks, and only one trial was publicly funded. This review found “low- to very low-quality evidence” that amphetamines reduced patient and clinician-rated ADHD symptoms, compared with placebo, but they were not better for retention in treatment. It found no evidence for a beneficial dose response. Amphetamines increased treatment withdrawal due to adverse effects (RR 2.69, 95% CI 1.63 to 4.45). The review also found no difference between IR and ER formulations for any outcome.

In 2018 Lancet Psychiatry published a very detailed SR/NMA of 133 RCTs of stimulants and non-stimulants in children, adolescents and adults.53 The authors also sought unpublished trials and information. For people ≥ 18, they assessed efficacy based on clinician ratings at 12 weeks. Reviewers identified 51 RCTs in adults (N=8,131 for efficacy analyses). Data were insufficient to assess treatment for > 12 weeks, and the authors identified very frequent risks of bias. The underlying RCTs assessed efficacy using heterogeneous symptom scales, but the meta-analysis did not include functional outcomes beyond the clinician’s subjective impression of improvement. For “tolerability” (withdrawal due to adverse effects), placebo was better tolerated than drug treatment. In contrast, at 12 weeks “acceptability” was better for amphetamines than placebo: the proportion who withdrew for any reason was lower (OR 0.68, 95% CI 0.49 to 0.95).

Overall, we find the available RCT results impossible to translate to clear estimates of harms and benefits that a clinician could find helpful during shared decision making with a patient. Systematic reviews generally find low certainty of evidence about benefits, a broad range of potential harms from drug therapy, and low external validity – the relation of results from RCTs to everyday clinical practice.

Evidence from observational studies

A population based study of Swedish national registries found that in people treated during 2006 with prescription stimulants, criminality was reduced during 2009.54 Using the same data sources, these authors also reported that medication appeared to reduce the increased risk of serious transport accidents associated with ADHD in males.55 Cochrane review authors pointed to contradictory evidence from observational studies, leaving uncertainty about the true effects of medications.37

Less reassuring is a recent meta-analysis of observational studies investigating the association between ADHD medications and risk of any cardiovascular disease (CVD).56 The authors identified 7 studies including adults. They estimated relative risk of CVD in children and adolescents (RR 1.18; 95% CI 0.91-1.53), in younger and middle-aged adults (RR, 1.04; 95% CI 0.43-2.48) and in older adults (RR 1.59, 95% CI 0.62-4.05). Increased CVD risk appears limited to people with a prior CVD history. The investigators interpret their findings as suggesting “no statistically significant association between ADHD medication use and the risk of any cardiovascular events” but caution that “a modest risk increase could not be excluded, especially for the risk of cardiac arrest or tachyarrhythmias,” and note limited information about long-term use.

Do ADHD medications affect substance use disorders?

Authors of the landmark Multimodal Treatment Study of ADHD in 579 children (MTA) followed participants recruited in 1994-1996 for up to 16 years to assess adult substance use (by confidential self-reporting) at a mean age of 25.57 They found no evidence that prescription stimulant treatment in childhood either increased or decreased frequent use of alcohol, cigarettes, marijuana, or other substance use in young adulthood. An earlier MA reached similar conclusions.58 The Swedish national registry study of people treated with stimulants in 2006 found no association with increased substance abuse in 2009, but a possible decrease.59 A study of US health care claims from 2005-2014 also found evidence that while patients were taking ADHD medications (compared with periods when they were not), concurrent substance-related events such as emergency department visits were less frequent: for males (OR 0.65; 95% CI, 0.64-0.67), and females (OR 0.69, 95% CI0.67-0.71).60

Evidence also limited for non-drug treatments

Evidence for non-pharmacological treatments such as cognitive behavioural therapy (CBT) is derived from very small RCTs. A 2020 SR/MA of 9 RCTs of CBT (N=386) claims superiority for ADHD symptoms of CBT vs no treatment or vs active control treatments.61 However there was extensive bias. Authors of the 2018 Lancet Psychiatry SR/NMA consider the lack of reliable evidence for non-drug treatments “highly problematic, in particular for those patients who do not opt for, or are unable to tolerate a pharmacologic treatment.”62 Their 2022 protocol for a new SR/NMA of drug and non-drug treatments for adult ADHD promises results as early as 2024. But it notes that unavailability of individual patient data and other data quality issues may preclude learning about effects on outcomes such as clear functional improvement.

In British Columbia, the Cognitive Behaviour Therapy (CBT) Skills Group Program provides publicly funded 8-week CBT sessions, including for adults with ADHD.63 Accredited CBT training is also available for physicians.

Is lisdexamfetamine better than other stimulants?

Health Canada approved lisdexamfetamine (Vyvanse) in 2013 to treat ADHD in adults. It is a prodrug, converted to d-amphetamine in the bloodstream by a red blood cell enzyme.64 The putative efficacy advantage of a smoother d-amphetamine concentration profile in blood has not been demonstrated, although it can be simulated by delaying an equivalent dose of IR d-amphetamine by 1 hour.65 Compared with ER mixed amphetamine salts (Adderall XR), unpublished experiments demonstrated by 2006 a similar (1-2 hour) delay in Tmax.66-67

The patent holder (Shire) sponsored a 2010 publication suggesting that as a prodrug requiring activation in the bloodstream, lisdexamfetamine might be less liable to intravenous or intra-nasal (“snorted”) abuse.68 However, Shire terminated prematurely in 2009 after enrolment of only 3 participants a more definitive experiment to compare subjective “drug liking” of the prodrug vs mixed amphetamine salts (Adderall XR). The experiment was halted “based on a non-safety related business priority decision.”69

Health Canada’s 2009 Summary Basis of Decision for approving lisdexamfetamine for children indicates no evidence of a therapeutic advantage over ER mixed amphetamine salts, and no dose response above 30mg/d for efficacy assessed by rating scales. No evidence was then available for treatment longer than 4 weeks.70 The 2023 product monograph refers to a 6-week withdrawal RCT (lisdexamfetamine vs placebo, N=116) sponsored, designed, analyzed, and written by the manufacturer (Shire).33,71

Amongst responders who had taken lisdexamfetamine for at least 6 months, people randomized to amphetamine withdrawal (placebo) rated their symptoms worse. Another Shire-controlled 10 week RCT claims slight improvement on a self-rated executive function scale in adults taking lisdexamfetamine vs placebo (N assessed = 154/161 randomized).72 Adverse events such as anorexia, dry mouth, headache, feeling jittery or irritable and insomnia were much higher in the lisdexamfetamine group, so that patient blinding is likely impossible. There is no evidence for an efficacy or safety advantage of lisdexamfetamine over other amphetamine formulations. However, Vyvanse costs up to 5-fold more than generic ER methylphenidate, and more than amphetamines.35

Vignette resolution: After discussion, you advise your patient that before proposing any diagnosis or considering alternative treatments, you require follow-up visits to obtain a detailed history and collateral information. Surprised by the “Important Safety Information” you showed him on the Vyvanse.com website2 – including the possibility of physical and psychological dependence – he accepts your cautious approach. Colleagues report similar experiences, and agree that your Division of Family Practice should arrange continuing education to facilitate careful diagnosis and responsible treatment of ADHD in your community.


Several BC experts reviewed the draft of this Therapeutics Letter for factual accuracy, and to ensure it is relevant to clinicians.
The UBC TI is funded by the BC Ministry of Health to provide evidence-based information about drug therapy. We neither formulate nor adjudicate provincial drug policies.
ISSN: 2369-8691
International Society of Drug Bulletin LogoThe Therapeutics Letter is a member of the International Society of Drug Bulletins (ISDB), a world-wide network of independent drug bulletins that aims to promote international exchange of quality information on drugs and therapeutics.

Disclaimer

All inferences, opinions and conclusions drawn in this manuscript are those of the authors and do not reflect the opinions or policies of the data stewards.


Data References

The following data sources were used (https://www2.gov.bc.ca/gov/content/health/conducting-health-research-evaluation/data-access-health-data-central): BC Ministry of Health [creator] (2023): Medical Services Plan (MSP) Payment Information File. BC Ministry of Health [publisher]. BC Ministry of Health (2022); BC Ministry of Health [creator] (2023): PharmaNet. BC Ministry of Health [publisher]. Data Stewardship Committee (2022); Canadian Institute for Health Information [creator] (2023): Discharge Abstract Database (Hospital Separations). BC Ministry of Health [publisher]. BC Ministry of Health (2022); BC Ministry of Health [creator] (2023): Consolidation File (MSP Registration & Premium Billing). BC Ministry of Health [publisher]. BC Ministry of Health (2022).


References

  1. Coey SH. Takeda accentuates the positives for adult ADHD patients in new ‘V is for Vyvanse’ campaign. Fierce Pharma September 17, 2020 https://www. fiercepharma.com/marketing/takeda-targets-adult-adhd-patients-new- vyvanse-campaign-focused-positives-symptom-control
  2. Takeda Pharmaceuticals U.S.A. Inc. Takeda USA website. https://vyvanse.com/
  3. Posner J, Polanczyk GV, Sonuga-Barke E. Attention-deficit hyperactivity disorder. Lancet 2020; 395(10222):450-462. DOI: 10.1016/S0140-6736(19)33004-1
  4. Therapeutics Initiative. What is the evidence for using CNS stimulants to treat ADHD in children? Therapeutics Letter 69 (Mar-May 2008). https://ti.ubc.ca/letter69
  5. Therapeutics Initiative. Atomoxetine for ADHD in children and adolescents. Therapeutics Letter 73 (Jan-Mar 2009). https://ti.ubc.ca/letter73
  6. Therapeutics Initiative. Stimulants for ADHD in children: Revisited. Therapeutics Letter 110 (Jan-Feb 2018). https://ti.ubc.ca/letter110
  7. Therapeutics Initiative. OROS methylphenidate (Concerta) for the treatment of children and adults with ADHD. Drug Assessment. April 23, 2010. https://www.ti.ubc.ca/2010/04/23/oros-methylphenidate-concerta-treatment-children-and-adults-adhd/
  8. Morrow RL, Garland EJ, Wright JM, et al. Influence of relative age on diagnosis and treatment of attention-deficit/hyperactivity disorder in children. CMAJ Canadian Medical Association Journal 2012; 184(7):755-62. DOI: 10.1503/cmaj.111619
  9. British Medical Journal. The known unknowns of ADHD (webinar). https://www.bmj.com/known-unknowns
  10. LeFever GB, Sawson KV, Morrow AL. The Extent of Drug Therapy for Attention Deficit-Hyperactivity Disorder Among Children in Public Schools. Am J Public Health 1999; 89(9):1359-1364. DOI: 10.2105/ajph.89.9.1359
  11. Thomas R, Mitchell GK, Batstra L. Attention-deficit/hyperactivity disorder: are we helping or harming? BMJ 2013; 347:f6172. DOI: 10.1136/bmj.f6172
  12. Kazda L, Bell K, Thomas R, McGeechan K, Sims R, Barratt A. Overdiagnosis of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Systematic Scoping Review. JAMA Network Open. 2021; 4(4):e215335. DOI: 10.1001/jamanetworkopen.2021.5335
  13. Kazda L, McGeechan K, Bell K, Thomas R, Barratt A. Increased diagnosis of attention-deficit hyperactivity disorder despite stable hyperactive/inattentive behaviours: evidence from two birth cohorts of Australian children. Journal of Child Psychology and Psychiatry 2023; 64:1140-1148. DOI: 10.1111/jcpp.13700
  14. Brault MC, Degroote E, Jean M, Van Houtte M. Relative Age Effect in Attention Deficit/Hyperactivity Disorder at Various Stages of the Medicalization Process. Children 2022; 9(6):889. DOI: 10.3390/children9060889
  15. Ponnou S, Thome B. ADHD diagnosis and methylphenidate consumption in children and adolescents: A systematic analysis of health databases in France over the period 2010–2019. Frontiers in psychiatry Frontiers Research Foundation 2022; 13:957242. DOI: 10.3389/fpsyt.2022.957242
  16. Layton TJ, Barnett ML, Hicks TR, Jena AB. Attention Deficit-Hyperactivity Disorder and Month of School Enrollment. New England Journal of Medicine 2018; 379(22):2122-2130. DOI: 10.1056/NEJMoa1806828
  17. Whitely M, Raven M, Timimi S, Jureidini J, Phillimore J et al. Attention deficit hyperactivity disorder late birthdate effect common in both high and low prescribing international jurisdictions: a systematic review. Journal of Child Psychology and Psychiatry 2019; 60:398-391. DOI: 10.1111/jcpp.12991
  18. Rogers MA, MacLean J. ADHD Symptoms Increased During the Covid-19 Pandemic: A Meta-Analysis. J Atten Disord. 2023 Jun; 27(8):800-811. DOI: 10.1177/10870547231158750
  19. Sluiter MN, de Vries YA, Koning LG, Hak E, Bos JHJ et al. A Prescription Trend Analysis of Methylphenidate: Relation to Study Reports on Efficacy. Administration and Policy in Mental Health and Mental Health Services Research (2020) 47:291–299. DOI: 10.1007/s10488-019-00983-6
  20. Sibley MH, Arnold LE, Swanson JM, et al. Variable Patterns of Remission from ADHD in the Multimodal Treatment Study of ADHD. American Journal of Psychiatry 2022; 179(2):142-151. DOI: 10.1176/appi.ajp.2021.21010032
  21. Sibley MH, Mitchell JT, Becker SP. Method of adult diagnosis influences estimated persistence of childhood ADHD: a systematic review of longitudinal studies. Lancet Psychiatry 2016; 3:1157-64. DOI: 10.1016/S2215-0366(16)30190-0
  22. Espinet SD, Graziosi G, Toplak ME, et al. A Review of Canadian Diagnosed ADHD Prevalence and Incidence Estimates Published in the Past Decade. Brain Sciences 2022; 12(8):1051. DOI: 10.3390/brainsci12081051
  23. Raman SR, Man KKC, Bahmanyar S, et al. Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases. The Lancet. Psychiatry 2018; 5(10):824-835. DOI:  10.1016/S2215-0366(18)30293-1
  24. Sibley MH. Why are stimulant medication prescriptions rising globally? The Lancet. Psychiatry 2018; 5(10):774-776. DOI:  10.1016/S2215-0366(18)30317-1
  25. Morkem R, Patten S, Queenan J, Barber D. Recent Trends in the Prescribing of ADHD Medications in Canadian Primary Care. Journal of Attention Disorders 2020; 24(2):301-308. DOI: 10.1177/1087054717720719 
  26. Chan AYL, Ma TT, Lau WCY, et al. Attention-deficit/hyperactivity disorder medication consumption in 64 countries and regions from 2015 to 2019: a longitudinal study. E Clinical Medicine 2023; 58:101780. DOI:  10.1016/j.eclinm.2022.101780
  27. Dunlop BW, Wu R, Helms K. Performance of the Adult ADHD Self-Report Scale-v1.1 in Adults with Major Depressive Disorder. Behavioral Sciences 2018; 8(4):37. DOI: 10.3390/bs8040037
  28. Canadian ADHD Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines. 4.1 Edition, Toronto ON; CADDRA, 2020.  https://adhdlearn.caddra.ca/wp-content/uploads/2022/08/Canadian-ADHD-Practice-Guidelines-4.1-January-6-2021.pdf
  29. Centre for Addiction and Mental Health (CAMH). Adult ADHD: Diagnosis. CAMH. https://www.camh.ca/en/professionals/treating-conditions-and-disorders/adult-adhd/adult-adhd—diagnosis
  30. Weiss MD. Weiss Functional Impairment Rating Scale (WFIRS) Instructions 2011. http://www.shared-care.ca/files/Weiss_Functional_Impairment_Self-Report.pdf
  31. Baerg Hall E. Adult ADHD – Practice Tip. This Changed My Practice: The University of British Columbia. October 27, 2021. https://thischangedmypractice.com/adult-adhd/
  32. Takeda Canada Inc. ADDERALL XR® (mixed salts amphetamine extended-release) Canadian product monograph. Dec. 21, 2020. https://pdf.hres.ca/dpd_pm/00059340.PDF
  33. Takeda Canada Inc. VYVANSE® (lisdexamfetamine) Canadian product monograph, revised April 3, 2023. https://assets-dam.takeda.com/image/upload/v1689362411/legacy-dotcom/siteassets/en-ca/home/what-we-do/our-medicines/product-monographs/vyvanse/vyvanse-pm-en.pdf
  34. Janssen Inc. CONCERTA® (methylphenidate hydrochloride extended-release) Canadian product monograph, revised May 29, 2023. https://janssen.com/canada/sites/www_janssen_com_canada/files/prod_files/live/concerta_cpm.pdf
  35. BC Provincial Academic Detailing (PAD) Service. Medications for ADHD: Focus on drug information. BC Provincial Academic Detailing (PAD) Service. October 2022. https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/pad-service/medications-for-adhd 
  36. Sandoz Canada Ind. Atomoxetine product monograph. Jan. 7, 2016. https://www.sandoz.ca/sites/www.sandoz.ca/files/Atomoxetine_Product_Monograph.pdf
  37. Boesen K, Paludan-Müller AS, Gøtzsche PC, Jørgensen KJ. Extended-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 2022 Issue 2. Art No.:CD012857. DOI: 10.1002/14651858.CD012857.pub2
  38. Moran LV, Ongur D, Hsu J, et al. Psychosis with Methylphenidate or Amphetamine in Patients with ADHD. New England Journal of Medicine 2019; 380(12):1128-1138. DOI: 10.1056/NEJMoa1813751
  39. Cortese S. Psychosis during Attention Deficit-Hyperactivity Disorder Treatment with Stimulants. New England Journal of Medicine 2019; 380(12):1178-1180.  DOI: 10.1056/NEJMe1900502
  40. Balcerac A, Baldacci A, Romier A, et al. Drug-induced delusion: A comprehensive overview of the WHO pharmacovigilance database. Psychiatry Research 2023; 327:115365.  DOI:  10.1016/j.psychres.2023.115365
  41. Lakhan SE, Kirchgessner A. Prescription stimulants in individuals with and without attention deficit hyperactivity disorder: misuse, cognitive impact, and adverse effects. Brain and Behavior 2012 Sep; 2(5):661-677. DOI: 10.1002/brb3.78 
  42. Cohen D, Recalt A. Discontinuing Psychotropic Drugs from Participants in Randomized Controlled Trials: A Systematic Review. Psychother Psychosom 2019; 88:96-104. DOI: 10.1159/000496733
  43. Recalt AM, Cohen D. Withdrawal Confounding in Randomized Controlled Trials of Antipsychotic, Antidepressant, and Stimulant Drugs, 2000-2017. Psychother Psychom 2019; 88:105-113. DOI: 10/1159/000496734
  44. Advokat C. What are the cognitive effects of stimulant medications? Emphasis on adults with attention-deficit/hyperactivity disorder (ADHD). Neurosci Biobehav Rev. 2010 Jul; 34(8):1256-66. DOI: 10.1016/j.neubiorev.2010.03.006
  45. Roberts CA, Jones A, Sumnall H, Gage SH, Montgomery C. How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and d-amphetamine. European Neuropsychopharmacology 2020; 38:40-62. DOI: 10.1016/j.euroneuro.2020.07.002
  46. Bowman E, Coghill D, Murawski C, Bossaerts P. Not so smart? “Smart” drugs increase the level but decrease the quality of cognitive effort. Sci Adv. 2023 Jun 16; 9(24):eadd4165. DOI: 10.1126/sciadv.add4165
  47. Pereira Ribeiro J, Arthur EJ, Gluud C, Simonsen E, Storebø OJ. Does Methylphenidate Work in Children and Adolescents with Attention Deficit Hyperactivity Disorder? Pediatr. Rep. 2021, 13, 434–443. DOI: 10.3390/pediatric13030050
  48. World Health Organization (WHO). WHO Model List of Essential Medicines – 23rd list, 2023 and WHO Model List of Essential Medicines for Children – 9th list, 2023. https://www.who.int/groups/expert-committee-on-selection-and-use-of-essential-medicines/essential-medicines-lists
  49. Pereira Ribeiro J, Lunde C, Gluud C, Simonsen E, Storebø OJ. Methylphenidate denied access to the WHO List of Essential Medicines for the second time. BMJ Evidence-Based Medicine 2022; DOI: 10.1136/bmjebm-2021-111862
  50. Cândido CF, Menezes de Padua A, Golder S, Junqueira DR. Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 2021, Issue 1. Art. No.: CD013011. DOI: 10.1002/14651858.CD013011.pub2
  51. Elliott J, Johnston A, Husereau D, et al. Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis. PLoS ONE 2020; 15(10):e0240584. DOI: 10.1371/journal.pone.0240584
  52. Castells X, Blanco-Silvente L, Cunill R. Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 2018, Issue 8. Art. No.: CD007813. DOI: 10.1002/14651858.CD007813.pub3
  53. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. The Lancet. Psychiatry 2018; 5(9):727-738. DOI: 10.1016/S2215-0366(18)30269-4
  54. Lichtenstein P, Halldner L, Zetterqvist J, et al. Medication for Attention Deficit Hyperactivity Disorder and Criminality.  New England Journal of Medicine 2012; 367(21):2006-14. DOI: 10.1056/NEJMoa1203241
  55. Chang Z, Lichtenstein P, D’Onofrio BM, et al. Serious transport accidents in adults with attention/deficit disorder and the effect of medication: a population-based study. JAMA Psychiatry. 2014;71(3):319-25. DOI: 10.1001/jamapsychiatry.2013.4174
  56. Zhang L, Yao H, Li L, Du Rietz E, Andell P et al. Risk of Cardiovascular Diseases Associated with Medications Used in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis. JAMA Network Open 2022; 5(11):e2243597. DOI: 10.1001/jamanetworkopen.2022.43597
  57. Molina BSG, Kennedy TM, Howard AL, et al. Association Between Stimulant Treatment and Substance Use Through Adolescence Into Early Adulthood. JAMA Psychiatry. 2023; 80(9):933-941. DOI: 10.1001/jamapsychiatry.2023.2157
  58. Humphreys KL, Eng T, Lee SS. Stimulant Medication and Substance Use Outcomes: A Meta-analysis. JAMA Psychiatry. 2013 July; 70(7):740–749. DOI: 10.1001/jamapsychiatry.2013.1273
  59. Chang Z, Lichtenstein P, Halldner L, et al. Stimulant ADHD medication and risk for substance abuse. Journal of Child Psychology & Psychiatry & Allied Disciplines 2014; 55(8):878-85. DOI: 10.1111/jcpp.12164
  60. Quinn PD, Chang Z, Hur K, et al. ADHD Medication and Substance-Related Problems. American Journal of Psychiatry 2017; 174(9): 877-885. DOI: 10.1176/appi.ajp.2017.16060686
  61. Young Z, Moghaddam N, Tickle A. The Efficacy of Cognitive Behavioral Therapy for Adults With ADHD: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Attention Disorders 2020; 24(6):875-888. DOI: 10.1177/1087054716664413
  62. Cortese S, Del Giovane C, Chamberlain S, et al. Pharmacological and non-pharmacological interventions for adults with ADHD: protocol for a systematic review and network meta-analysis. BMJ Open 2022; 12(3):e058102. DOI: 10.1136/bmjopen-2021-058102
  63. Shared Care Committee and UBC Office of Continuing Professional Development. CBT Skills Groups for BC Residents. https://cbtskills.ca/about-us/what-we-offer/
  64. Ermer JC, Pennick M, Frick G. Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy. Clinical Drug Investigation 2016; 36(5):341-56. DOI: 10.1007/s40261-015-0354-y
  65. Dolder PC, Strajhar P, Vizeli P, et al. Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects. Frontiers in Pharmacology 2017; 8:617. DOI: 10.3389/fphar.2017.00617
  66. Jasinski D, Krishnan S. Pharmacokinetics of Oral Lisdexamfetamine Dimesylate (LDX; NRP104) Versus d-Amphetamine Sulfate in Healthy Adults With a History of Stimulant Abuse (NRP104.A01). https://www.sec.gov/Archives/edgar/data/1288379/000114036106009298/ex99_1.htm
  67. Goodman DW. Lisdexamfetamine Dimesylate: The First Prodrug Stimulant. Psychiatry 2007; 4(8):39–45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880945/
  68. Goodman DW. Lisdexamfetamine dimesylate (vyvanse), a prodrug stimulant for attention-deficit/hyperactivity disorder. P&T 2010; 35(5):273-87.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873712/ 
  69. Shire Inc. Compare Subjective Drug Liking & Pharmacokinetics of Vyvanse™ and ADDERALL XR® When Administered as an Oral Solution. ClinicalTrials.gov ID NCT00776555. https://classic.clinicaltrials.gov/ct2/show/NCT00776555 
  70. Health Canada. Summary Basis for Decision 2010. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailOne.php?linkID=SBD00311
  71. Brams M, Weisler R, Findling RL, et al. Maintenance of efficacy of lisdexamfetamine dimesylate in adults With attention-deficit/hyperactivity disorder: randomized withdrawal design. Journal of Clinical Psychiatry 2012; 73(7):977-83. DOI: 10.4088/JCP.11m07430
  72. Adler LA, Dirks B, Deas PF, et al. Lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry 2013; 74(7):694-702.  DOI: 10.4088/JCP.12m08144
3 Comments
  • CBC
    Posted at 01:32h, 03 October Reply

    CBC: More adults are taking medication for ADHD. Physicians say trend is a double-edged sword
    Patients say ADHD medications can be life-changing, while others warn of health risks, dependance.
    by Laura Pelley, posted: October 3, 2023
    https://www.cbc.ca/news/health/more-adults-are-taking-medication-for-adhd-physicians-say-trend-is-a-double-edged-sword-1.6984578

  • Andrea Woo
    Posted at 08:40h, 03 October Reply

    The Globe and Mail: B.C. seeing surge in stimulant drugs being prescribed for adult ADHD
    by Andrea Woo, published: October 3, 2023
    https://www.theglobeandmail.com/canada/article-adult-adhd-medication-increase/

  • Janet Currie
    Posted at 09:48h, 06 October Reply

    This is one of the best letters you have ever done – salient points, strong conclusions and very accessible in terms of language and concepts. I get asked for information like this frequently, but it is hard to assemble the information.

    Janet Currie MSW, PhD
    Research Collaborator, School or Nursing
    University of British Columbia

    Dr. Currie declares no relationships with pharmaceutical companies. She is owner and manager of Psychmedaware.org and Coordinator of the Psychiatric Medication Awareness Group, and developed a booklet “What people need to know about psychiatric drugs” in 2022 with funds donated to UBC for education and training.

Post A Comment