Attention-deficit/hyperactivity Disorder Pharmacotherapy Research Articles

ADHD Pharmacotherapy and Mortality in Individuals With ADHD

Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risks of adverse health outcomes including premature death, but it is unclear whether ADHD pharmacotherapy influences the mortality risk. To investigate whether initiation of ADHD pharmacotherapy was associated with reduced mortality risk in individuals with ADHD. In an observational nationwide cohort study in Sweden applying the target trial emulation framework, we identified individuals aged 6 through 64 years with an incident diagnosis of ADHD from 2007 through 2018 and no ADHD medication dispensation prior to diagnosis. Follow-up started from ADHD diagnosis until death, emigration, 2 years after ADHD diagnosis, or December 31, 2020, whichever came first. ADHD medication initiation was defined as dispensing of medication within 3 months of diagnosis. We assessed all-cause mortality within 2 years of ADHD diagnosis, as well as natural-cause (eg, physical conditions) and unnatural-cause mortality (eg, unintentional injuries, suicide, and accidental poisonings). Of 148 578 individuals with ADHD (61 356 females [41.3%]), 84 204 (56.7%) initiated ADHD medication. The median age at diagnosis was 17.4 years (IQR, 11.6-29.1 years). The 2-year mortality risk was lower in the initiation treatment strategy group (39.1 per 10 000 individuals) than in the noninitiation treatment strategy group (48.1 per 10 000 individuals), with a risk difference of -8.9 per 10 000 individuals (95% CI, -17.3 to -0.6). ADHD medication initiation was associated with significantly lower rate of all-cause mortality (hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.88) and unnatural-cause mortality (2-year mortality risk, 25.9 per 10 000 individuals vs 33.3 per 10 000 individuals; risk difference, -7.4 per 10 000 individuals; 95% CI, -14.2 to -0.5; HR, 0.75; 95% CI, 0.66 to 0.86), but not natural-cause mortality (2-year mortality risk, 13.1 per 10 000 individuals vs 14.7 per 10 000 individuals; risk difference, -1.6 per 10 000 individuals; 95% CI, -6.4 to 3.2; HR, 0.86; 95% CI, 0.71 to 1.05). Among individuals diagnosed with ADHD, medication initiation was associated with significantly lower all-cause mortality, particularly for death due to unnatural causes.

Pharmacotherapy for ADHD in children and adolescents: A summary and overview of different European guidelines.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. It is the most common neurodevelopmental disorder presenting to pediatric services, and pediatricians are often involved in the early assessment, diagnosis, and treatment of children with ADHD. The treatment of ADHD typically involves a multimodal approach that encompasses a combination of psychoeducation, parent/teacher training, psychosocial/psychotherapeutic interventions, and pharmacotherapy. Concerning pharmacotherapy, guidelines vary in drug choice and sequencing, with psychostimulants, such as methylphenidate and (lis)dexamfetamine, generally being the favored initial treatment. Alternatives include atomoxetine and guanfacine. Pharmacotherapy has been proven effective, but close follow-up focusing on physical growth, cardiovascular monitoring, and the surveillance of potential side effects including tics, mood fluctuations, and psychotic symptoms, is essential. This paper presents an overview of current pharmacological treatment options for ADHD and explores disparities in treatment guidelines across different European countries. Conclusion: Pharmacological treatment options for ADHD in children and adolescents are effective and generally well-tolerated.Pharmacotherapy for ADHDis alwayspart of a multimodal approach.While there is a considerableconsensus among European guidelines on pharmacotherapy for ADHD, notable differences exist, particularly concerning the selection and sequencing of various medications. What is Known: • There is a significant base of evidence for pharmacological treatment for ADHD in children and adolescents. • Pediatricians are often involved in assessment, diagnosis and management of children with ADHD. What is New: • Our overview of different European guidelines reveals significant agreement in the context of pharmacotherapy for ADHD in children and adolescents. • Discrepancies exist primarily in terms of selection and sequencing of different medications.

Factors associated with pharmacological treatment in children with attention-deficit/hyperactivity disorders: a retrospective study of a series of 77 cases in a single third-level reference Centre in Apulia region

BackgroundThe present study analysed data on children and adolescents with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) who were referred to the ADHD reference centre of Scientific Institute IRCCS E. Medea (Brindisi, Italy) for ADHD pharmacotherapy initiation and monitoring overtime. The main aim of the study was to examine differences in pharmacological treatment status (i.e., treatment continuation vs discontinuation) between patients.MethodsSeventy-seven children and adolescents (mean age at pharmacotherapy initiation = 9.5, standard deviation = 2.6) with ADHD received drugs treatment for ADHD at the reference center between January, 2013 and May, 2022. Demographic and clinical data were obtained from the Italian Registry for ADHD and medical records. Child Behavior Checklist (CBCL) available data were used.ResultsPharmacological treatment status was examined for patients (n = 63) with at least 12 months of follow-up after the first pharmacological treatment for ADHD. After starting pharmacotherapy treatment, 77.8% (n = 49) patients were still on treatment whereas 22.2% (n = 14) discontinued it. No between group difference were observed in demographic and clinical data except for the intelligence quotient/intellectual disability and rule-breaking behavior (n = 40).ConclusionsThis study stressed the need of periodical assessments, monitoring difficulties with treatment and/or reasons for poor treatment compliance to provide individualized care.

Trends in Attention-Deficit Hyperactivity Disorder Diagnosis and Pharmacotherapy Among Adults With Opioid Use Disorder.

This study aimed to assess nationwide trends in attention-deficit hyperactivity disorder (ADHD) diagnoses and pharmacotherapy among patients with opioid use disorder and ADHD and to examine factors predicting receipt of stimulant medications among patients receiving medications for opioid use disorder (MOUDs). A claims-based database of commercially insured patients ages 13-64 was used to conduct two analyses: an annual cross-sectional study of 387,980 patients diagnosed as having opioid use disorder (2007-2017) to estimate the prevalence of ADHD diagnoses and pharmacotherapy, and a retrospective cohort study of 158,591 patients receiving MOUDs to test, with multivariable regression, the association between patient characteristics and receipt of stimulant medication. From 2007 to 2017, the prevalence of ADHD diagnoses increased from 4.6% to 15.1% and the rate of ADHD pharmacotherapy increased from 42.6% to 51.8% among patients with opioid use disorder. Among all patients receiving MOUDs, 10.5% received at least one prescription stimulant during the study period. Female sex; residence in the southern United States; and ADHD, mood, and anxiety disorder diagnoses were associated with increased likelihood of stimulant receipt. Stimulant use disorder and other substance use disorder diagnoses were associated with decreased likelihood of stimulant receipt. ADHD diagnoses and pharmacotherapy among patients with opioid use disorder have increased. A minority of patients with ADHD and taking MOUDs received a stimulant. Further study is needed of the benefits and risks of ADHD pharmacotherapy for patients with opioid use disorder.

Expert consensus on the diagnosis and treatment of adult attention deficit hyperactivity disorder in China (2023 Edition)

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in school-age children, with 30%-50% persisting into adulthood. In addition, adult ADHD patients have more comorbidities, are more difficult to identify, and have a wider range of impairments on individual function, thereby leading to more serious adverse effects on medical care, economy and society. This consensus establishes the diagnose of adult ADHD based on the 11th edition of International Classification of Diseases (ICD-11), determines the treatment plans based on the etiology and pathogenesis of the disease, recommends psycho-stimulants as the first-line pharmacotherapy for adult ADHD and selective noradrenalin reuptake inhibitors (NARIs) as the second-line pharmacotherapy to reduce the core symptoms, and combines non-pharmacological treatments, such as cognitive behavioral therapy, health education and lifestyle training, aiming to improve patients' functioning and quality of life to the utmost.

Type of medication therapy for ADHD and stimulant misuse during adolescence: a cross-sectional multi-cohort national study

Attention-deficit/hyperactivity disorder (ADHD) is associated with higher substance use rates. Stimulant and non-stimulant pharmacotherapy improve adolescent ADHD, but their associations with prescription stimulant misuse (PSM), cocaine, and methamphetamine use are unclear. Using 2005-2020 US Monitoring the Future data, we investigated relationships between ADHD pharmacotherapy history and PSM, cocaine, or methamphetamine use. Secondary students (13-19 years) provided data on pharmacotherapy history (N=199,560; 86.3% of total sample) between January 1, 2005 and May 31, 2020 in a cross-sectional multi-cohort study; weights assured a nationally representative sample. Participants were grouped by ADHD pharmacotherapy history: none (88.7%; principally non-ADHD controls); stimulant-only (5.8%); non-stimulant-only (3.3%); both stimulant and non-stimulant (2.1%). Outcomes were past-year PSM, cocaine, and methamphetamine use. Logistic regressions examined relationships between pharmacotherapy history and outcomes, controlling for sociodemographics, recent substance use, and stimulant treatment cessation. Past-year outcome rates were lowest in adolescents with no pharmacotherapy history: 4.7% for PSM [8310/174,561], 1.6% for cocaine [2858/174,688], and 0.7% for methamphetamine [1036/148,378]. A history of both stimulant and non-stimulant treatment was associated with the highest rates: 22.3% for PSM [940/4098], 10.4% for cocaine [450/4110], and 7.8% for methamphetamine [275/3427]. Adolescents who received monotherapy (stimulant- or non-stimulant-only) had intermediate rates, with no differences between monotherapy groups. While elevated PSM and illicit stimulant use rates are likely influenced by ADHD, our findings suggested adolescents with a history of both stimulant and non-stimulant pharmacotherapy are at highest risk for these stimulant outcomes. Adolescents receiving ADHD pharmacotherapy should be monitored for PSM and illicit stimulant use. National Institute on Drug Abuse/National Institutes of Health (USA) and Food and Drug Administration (USA).

Prescribing patterns for attention deficit hyperactivity disorder among children and adolescents in Taiwan from 2004 to 2017

This study documented the prescribing patterns of methylphenidate and atomoxetine among patients aged 3 to 18 in Taiwan diagnosed with attention deficit hyperactivity disorder (ADHD) between 2004 and 2017. Initial treatment for ADHD, the time between the first diagnosis and the first prescription, and medication-switching patterns were investigated. The final cohort consisted of 256,882 patients, and 147,210 (57.3%) of them received medication treatment. Most of the patients (98.2%) received methylphenidate. Atomoxetine use increased from 0.1% in 2007 to 5.5% in 2017. The median time between the ADHD diagnosis and the first prescription was 21 days (IQR: 0-212 days). In patients who initiated methylphenidate, 12,406 (8.4%) patients switched to atomoxetine; 850 (31.3%) of the children began with atomoxetine and switched to methylphenidate. In conclusion, methylphenidate was the predominant treatment for ADHD in 2004-2017. However, the prevalence of pharmacotherapy for ADHD was relatively low. Further investigation on the reasons behind this pattern is recommended.

Diagnosis and treatment of intractable idiopathic orofacial pain with attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP.

Effect of Past Pharmacotherapy for Attention-Deficit/Hyperactivity Disorder on Substance Use Disorder

Background: Substance use disorders (SUDs) are a considerable public health problem. Attention-deficit/hyperactivity disorder (ADHD) frequently occurs in patients with SUD. Several studies demonstrated that ADHD constitutes a significant risk factor for the development of SUDs and suggest that childhood ADHD pharmacotherapy might help prevent development of SUD. Objectives: The study aimed to explore the effect of childhood ADHD pharmacotherapy on later life’s functional impairment and substance use patterns. Methods: Treatment-seeking SUD patients with ADHD (n = 52) were recruited from various rehabilitation facilities in South Africa. Adult ADHD individuals without SUD (n = 48) were recruited from clinicians, retail pharmacies, and the general public. SUD participants in rehabilitation facilities were screened for and diagnosed with ADHD. Lifetime substance use was assessed using self-report. ADHD-related functional impairment was assessed by the Weiss Functional Impairment Rating Scale (WFIRS). Information on present and lifetime use of ADHD medication was obtained. Clinical outcomes between those with and without a history of ADHD pharmacotherapy were compared. Results: Medicated participants (n = 59) showed lower levels of ADHD-related impairment across all functional domains (p < 0.001), compared to non-medicated participants (n = 41). They also consumed less alcohol (p = 0.04), cannabis (p < 0.001), and illicit drugs (p = 0.006) compared to the non-medicated group. Furthermore, medicated participants had a lower frequency of tobacco use compared to non-medicated participants (p = 0.04). ADHD patients without SUD also more often received medication (100% vs. 18.6%; p < 0.001) and for a longer time (121.10 vs. 9.52 months; p < 0.001). Conclusion: Childhood ADHD pharmacotherapy might be associated with a decreased risk for substance use in adulthood and lower ADHD-related impairment. Despite study limitations, these findings underline the importance of early ADHD detection and treatment, which might prevent SUD.

Viloxazine, a Non-stimulant Norepinephrine Reuptake Inhibitor, for the Treatment of Attention Deficit Hyperactivity Disorder: A 3 Year Update.

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in childhood. Current treatment options for ADHD include pharmacological treatment (stimulants, non-stimulants, anti-depressants, anti-psychotics), psychological treatment (behavioral therapy with or without parent training, cognitive training, neurofeedback), and complementary and alternative therapies (vitamin supplementation, exercise). Central nervous system (CNS) stimulants are the primary pharmacological therapy used in treatment; however, these stimulant drugs carry a high potential for abuse and severe psychological/physical dependence. Viloxazine, a non-stimulant medication without evidence of drug dependence, is a selective norepinephrine reuptake inhibitor that has historically been prescribed as an anti-depressant medication. The extended-release (ER) form was approved by the US Food and Drug Administration (FDA) in April 2021 for the treatment of ADHD in pediatric patients aged 6-17 years. Phase 2 and 3 randomized control trials have demonstrated significant efficacy of viloxazine in improving ADHD symptoms versus placebo. Related to its long-standing use as an antidepressant, the safety profile and pharmacokinetics of viloxazine are well understood. Viloxazine appears to be a suitable alternative to current standard-of-care pharmacotherapy for ADHD, but the further investigation remains to be done in comparing its efficacy to that of current treatments.

Cardiovascular risk factors in attention-deficit/hyperactivity disorder: A family design study of Swedish conscripts.

(1) investigate the associations of attention-deficit/hyperactivity disorder (ADHD) with systolic and diastolic blood pressure, resting heart rate, pulse pressure (PP), physical fitness, and BMI; (2) explore whether cardiovascular risk factors and ADHD share genetic and environmental influences; (3) assess if pharmacological treatment for ADHD influences these associations. We identified 395,978 individuals born between 1973 and 1991 who had military conscription examinations at a mean age of 18.3years (SD=0.57) and their full-siblings within the same cohort (N=208,060) by linking population-based registers in Sweden. Significantly increased risk of ADHD was observed in individuals with low systolic blood pressure (SBP) and PP, low physical fitness, and in those who had overweight or obesity after adjustments (adjusted Odds Ratio [OR] ranging from 1.10 to 1.45). Full siblings of individuals with low SBP, low physical fitness, and obesity were more likely to receive an ADHD diagnosis compared to full siblings without those risk factors (OR ranging from 1.17 to 1.31). Additionally, analyses showed robust associations between ADHD and low SBP, low physical fitness, and obesity, even in ADHD medication-naïve individuals. Individuals with several cardiovascular risk factors are more often diagnosed with ADHD, regardless of psychiatric comorbidity. These association are not explained by ADHD pharmacotherapy, rather, they are in part due to shared familial risk factors.

A Dopamine D1 Agonist Versus Methylphenidate in Modulating Prefrontal Cortical Working Memory.

Methylphenidate is used widely to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants has significant side effects. This study used a rodent model (spontaneously hypertensive rat) of spatial working memory (sWM) to compare the effects of methylphenidate with the novel dopamine D1-like receptor agonist 2-methyldihydrexidine. Acute oral administration of methylphenidate (1.5 mg/kg) caused sWM improvement in half of the tested rats, but impairment in the others. Both improvement or impairment were eliminated by administration of the D1 antagonist SCH39266 directly into the prefrontal cortex (PFC). Conversely, 2-methyldihydrexidine showed greater sWM improvement compared with methylphenidate without significant impairment in any subject. Its effects correlated negatively with vehicle-treated baseline performance (i.e., rats with lower baseline performance improved more than rats with higher baseline performance). These behavioral effects were associated with neural activities in the PFC. Single neuron firing rate was changed, leading to the alteration in neuronal preference to correct or error behavioral responses. Overall, 2-methyldihydrexidine was superior to methylphenidate in decreasing the neuronal preference, prospectively, in the animals whose behavior was improved. In contrast, methylphenidate, but not 2-methyldihydrexidine, significantly decreased neuronal preference, retrospectively, in those animals who had impaired performance. These results suggest that a D1 agonist may be more effective than methylphenidate in regulating sWM-related behavior through neural modulation of the PFC, and thus may be superior to methylphenidate or other stimulants as ADHD pharmacotherapy. SIGNIFICANCE STATEMENT: Methylphenidate is effective in ADHD by its indirect agonist stimulation of dopamine and/or adrenergic receptors, but the precise effects on specific targets are unclear. This study compared methylphenidate to a dopamine D1 receptor-selective agonist by investigating effects on working memory occurring via neural modulation in the prefrontal cortex. The data suggest that pharmacological treatment selectively targeting the dopamine D1 may offer a superior approach to ADHD pharmacotherapy.

New Drugs to Treat ADHD: Opportunities and Challenges in Research and Development.

Since the landmark MTA (Multimodal Treatment of ADHD) trial unequivocally demonstrated the efficacy of methylphenidate, catecholaminergic drugs, especially stimulants, have been the therapeutic mainstay in treatment of Attention-Deficit Hyperactivity Disorder (ADHD). We review the new drugs which have entered the ADHD formulary. The lessons learned from drug-candidates that have succeeded in clinical trialstogether with those that have not have also been considered. What emerges confirms and consolidates the hypothesis that clinically effective ADHD drugs indirectly or directly increase catecholaminergic neurotransmission in the prefrontal cortex (PFC). Attempts to enhance catecholaminergic signalling through modulatory neurotransmitter systems or cognitive-enhancing drugs have all failed. New drugs approved for ADHD are catecholaminergic reuptake inhibitors and releasing agents, or selective noradrenaline reuptake inhibitors. Triple reuptake inhibitors with preferential effects on dopamine have not been successful. The substantial number of failures probably accounts for a continued focus on developing novel catecholaminergic and noradrenergic drugs, and a dearth of drug-candidates with novel mechanisms entering clinical development. However, substantial improvements in ADHD pharmacotherapy have been achieved by the almost exclusive use of once-daily medications and prodrugs, e.g. lisdexamfetamine and Azstarys®, which improve compliance, deliver greater efficacy and reduce risks for diversion and abuse.

A retrospective medical chart review of clinical outcomes in children and adolescents with attention-deficit/hyperactivity disorder treated with guanfacine extended-release in routine Canadian clinical practice

ObjectiveThis study evaluated clinical outcomes in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with the α2-adrenoceptor agonist guanfacine extended-release (GXR) in routine Canadian clinical practice.MethodsThis retrospective chart review focused on patients with ADHD aged 6–17 years initiating treatment with GXR as monotherapy or adjunctive therapy. Patients were followed for up to 12 months after GXR initiation and, if they had received prior ADHD pharmacotherapy, for 12 months before GXR initiation. The primary outcome was change in ADHD symptoms and functionality based on physician assessments, classified as improvement, no change, or worsening relative to the time of GXR initiation. Treatment-emergent adverse events (TEAEs) were evaluated. Clinical outcomes were also analyzed post hoc according to whether GXR treatment was received as monotherapy or adjunctive therapy, and by select psychiatric comorbidities. Exploratory analyses were conducted in patients who had received prior ADHD pharmacotherapy to evaluate clinical outcomes after initiating GXR.ResultsImprovements in ADHD symptoms were reported for 232/330 (70.3%) patients. Functional improvements in school performance and home life were reported for 213/330 (64.5%) and 209/330 (63.3%) patients, respectively. The most frequent TEAEs (≥ 5%) were somnolence, headache, insomnia, presyncope, and decreased appetite. Improvements in ADHD symptoms were observed when GXR was received as either monotherapy (35/60 [58.3%]) or adjunctive therapy (197/270 [73.0%]). Improvements in ADHD symptoms and functionality were observed in the majority of patients with select psychiatric comorbidities. Among patients who had experienced worsening of symptoms with prior ADHD pharmacotherapy, 44/54 (81.5%) experienced symptom improvement, 33/44 (75.0%) who had previously experienced worsening of school performance improved, and 34/48 (70.8%) who had previously experienced worsening of home life improved.ConclusionIn Canadian routine clinical practice, most children and adolescents with ADHD treated with GXR experienced improvements in ADHD symptoms and in functionality both at school and at home.

Treatment of Adolescents with Concurrent Substance Use Disorder and Attention-Deficit/Hyperactivity Disorder: A Systematic Review.

Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for the development of substance abuse and substance use disorders (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment, and is associated with poor treatment outcomes. In this study, we provide a systematic review of controlled studies on the effectiveness of pharmacological, psychosocial, and complementary treatments of ADHD in adolescents with and without comorbid SUD. In addition, we review the longitudinal association between pharmacotherapy for childhood ADHD and the development of SUD in adolescence and early adulthood. We conducted a systematic review of the research literature published since 2000 using Medline, PsycINFO, and the Cochrane Database of Systematic Reviews databases to select randomized clinical trials, observational studies, and meta-analyses. The quality of the evidence from each study was rated using the SIGN grading system. Based on the limited evidence available, strong clinical recommendations are not justified, but provisionally, we conclude that stimulant treatment in children with ADHD may prevent the development of SUD in adolescence or young adulthood, that high-dose stimulant treatment could be an effective treatment for adolescents with ADHD and SUD comorbidity, that cognitive behavior therapy might have a small beneficial effect in these patients, and that alternative treatments are probably not effective. More studies are needed to draw definitive conclusions that will allow for strong clinical recommendations.

Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences. Implications for impulsive-control disorders

Polymorphic alleles of the human dopamine D4 receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α2A adrenoceptor (α2AR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D4 receptor (D4R) and α2AR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D4R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α2AR forms functional heteromers with D4R and weather these heteromers show different properties depending on the D4R variant involved. Using cortical brain slices from hD4.7R knock-in and wild-type mice, here, we demonstrate that α2AR and D4R heteromerize and constitute a significant functional population of cortical α2AR and D4R. Moreover, in cortical slices from wild-type mice and in cells transfected with α2AR and D4.4R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD4.7R knock-in mice and in cells expressing the D4.7R polymorphic variant. We also show a lack of efficacy of D4R ligands to promote G protein activation and signaling only within the α2AR-D4.7R heteromer. Taken together, our results suggest that α2AR-D4R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.

Evaluation of Attention-Deficit/Hyperactivity Disorder Medications, Externalizing Symptoms, and Suicidality in Children

Childhood suicidality (ie, suicidal ideation or attempts) rates are increasing, and attention-deficit/hyperactivity disorder (ADHD) and externalizing symptoms are common risk factors associated with suicidality. More data are needed to describe associations of ADHD pharmacotherapy with childhood suicidality. To investigate the associations of ADHD pharmacotherapy with externalizing symptoms and childhood suicidality. In this cohort study, cross-sectional and 1-year-longitudinal associations were examined using data (collected during 2016-2019) from the Adolescent Brain Cognitive Development (ABCD) Study, a large, diverse US sample of children aged 9 to 11 years. Data analysis was performed from November to December 2020. Main and interaction associations of externalizing symptoms (hyperactivity ADHD symptoms, oppositional defiant, and conduct disorder symptoms) and ADHD medication treatment (methylphenidate and amphetamine derivatives, α-2-agonists, and atomoxetine) at baseline assessment. Child-reported suicidality (past and present at baseline; current at longitudinal assessment). Covariates were age, sex, race/ethnicity, parents' education, marital status, and concomitant child psychiatric pharmacotherapy (antidepressants and antipsychotics). Among 11 878 children at baseline assessment (mean [SD] age, 9.9 [0.6] years; 6196 boys [52.2%]; 8805 White [74.1%]), 1006 (8.5%) were treated with ADHD medication and 1040 (8.8%) reported past or current suicidality. Externalizing symptoms (median [range], 1 [0-29] symptom count) were associated with suicidality (for a change of 1 SD in symptoms, odds ratio [OR], 1.34; 95% CI, 1.26-1.42; P < .001), as was ADHD medication treatment (OR, 1.32; 95% CI, 1.06-1.64; P = .01). ADHD medication use was associated with less suicidality in children with more externalizing symptoms (significant symptom-by-medication interaction, B = -0.250; SE = 0.086; P = .004), such that for children who were not receiving ADHD medications, there was an association between more externalizing symptoms and suicidality (for a change of 1 SD in symptoms, OR, 1.42; 95% CI, 1.33-1.52; P < .001); however, for children who were receiving ADHD medication, there was no such association (OR, 1.15; 95% CI, 0.97-1.35; P = .10). The association with medication remained even when covarying for multiple confounders, including risk and protective factors for suicidality in ABCD, and was replicated in 1-year longitudinal follow-up. Sensitivity analyses matching participants with high numbers of externalizing symptoms taking and not taking ADHD medication treatment confirmed its association with less suicidality. These findings suggest that ADHD medication treatment is associated with less suicidality in children with substantial externalizing symptoms and may be used to inform childhood suicide prevention strategies.

Naturalistic exploratory study of the associations of substance use on ADHD outcomes and function

BackgroundAlthough Attention Deficit Hyperactivity Disorder (ADHD) is associated with an increased risk of substance use disorder (SUD), existing literature on how SUD interacts with ADHD outcomes is limited. This study investigates whether SUD among individuals with ADHD is associated with worse ADHD outcomes and prognosis, and the association between overall functioning and SUD. In addition, we seek to understand whether heavy cannabis use is a better predictor of poorer outcomes compared to SUD status alone.MethodWe conducted a retrospective analysis on 50 ADHD patient charts, which were allocated based on SUD status. Subgroup analysis was performed on the total sample population, with allocation based on heavy cannabis use. Mann-Whitney and Chi-Square tests were used for both the primary and subgroup analyses.ResultsSUD status highly correlated with more ADHD-related cognitive impairments and poorer functional outcomes at the time of diagnosis. ADHD patients with comorbid ADHD-SUD scored significantly lower (p = < 0.0001) on objective cognitive testing (Integrated Auditory and Visual Continuous Performance Test (IVA/CPT)) than ADHD patients without SUD. The correlation with poorer ADHD outcomes was more pronounced when groups were allocated based on heavy cannabis use status; in addition to significantly lower IVA/CPT scores (p = 0.0011), heavy cannabis use was associated with more severe fine motor hyperactivity and self-reported hyperactivity/impulsivity scores (p = 0.0088 and 0.0172, respectively).ConclusionFuture research is needed to determine how substance abuse can be a barrier to improved ADHD outcomes, and the effect cannabis and other substances have on cognitive function and pharmacotherapy of ADHD.

First-Time Users of ADHD Medication Among Children and Adolescents in Germany: An Evaluation of Adherence to Prescribing Guidelines Based on Claims Data.

Background: Drug utilization studies based on real-world data are vital for the identification of potentially needed improvements to rational prescribing. This is particularly important for the pharmacological treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD) due to the associated potential side effects and the frequent use. Whereas prevalent use is well-characterized, studies on first-time use of ADHD medication are scarce. This study aimed to evaluate off-label prescribing in first-time users of ADHD medication among children and adolescents in Germany based on three criteria: (i) lack of a documented ADHD diagnosis; (ii) first-time pharmacological treatment with a second-line drug; and (iii) patient age below 6 years.Methods: Based on German claims data, we included children and adolescents aged 0–17 years with a first-time dispensation of any ADHD medication in the period 2015–2017. These first-time users were characterized with regard to sex, age, specialty of the prescribing physician, documentation of an ADHD diagnosis, psychiatric hospitalization, psychiatric comorbidities, and history of other psychopharmacological drugs at first-time use.Results: The study population comprised 18,703 pediatric first-time users of ADHD medication. Of these, 9.8% had no documented ADHD diagnosis. Most of the ADHD drug users received first-line ADHD pharmacotherapy (methylphenidate, atomoxetine), whereas 2.6% were prescribed second-line ADHD medication (lisdexamfetamine, guanfacine, dexamfetamine, multiple ADHD drugs) as first drug. Overall, 1.2% of first-time users were aged below 6 years. A total of 12.7% of the study population met any off-label criterion.Conclusions: About 13% of pediatric first-time users of ADHD medication in Germany received an off-label pharmacotherapy at first-time use. Prescribing ADHD medication without a confirmed ADHD diagnosis was the most common of the three assessed off-label criteria. Off-label prescribing regarding drug choice and age of patients only occurred in a small percentage of initial pharmacological ADHD treatment. Our results suggest the need for improvement in rational prescribing, especially with regard to diagnostic requirements.

Disruption of Pharmacotherapy During the Transition from Adolescence to Early Adulthood in Patients with Attention-Deficit/Hyperactivity Disorder: A Claims Database Analysis Across the USA.

Background and ObjectiveAttention-deficit/hyperactivity disorder (ADHD) treatment rates in adults are low, possibly owing to discontinuation of pediatric care due to various circumstances (including inadequate health insurance coverage, poor disease insight, and patient/family resistance, as well as those who manage their ADHD independent of pharmacologic intervention) during the transition from adolescence to adulthood. To improve the understanding of treatment patterns during this transition, this study characterized pharmacotherapy use in patients with ADHD aged 16–21 years.MethodsA retrospective claims analysis of the IBM® MarketScan® Commercial Databases, which represent all census regions of the USA, included patients aged 16–21 years with two or more ADHD diagnoses between 1/1/2008 and 12/31/2017 (one or more diagnoses during the year of age 17) who were continuously enrolled from ages 16–21 years and prescribed ADHD medication for ≥ 6 months at age 17 years. Pharmacotherapy use was assessed longitudinally. Comparisons between ages were conducted using Wilcoxon signed-rank tests and McNemar tests. Treatment discontinuation was estimated using Kaplan–Meier analyses.ResultsThe analysis included 10,292 patients. The overall percentage of patients receiving pharmacotherapy significantly decreased (p < 0.001, regardless of treatment type and presence of co-occurring psychiatric disorders) as patients aged, with a median time to treatment discontinuation of 2.94 years. Among patients using pharmacotherapy at the age of 17 years, more than 30% were no longer using pharmacotherapy at age 21 years. As patients aged, the percentage using long-acting amphetamines or methylphenidates decreased, and the percentage receiving no treatment increased. The percentage of patients with disrupted treatment from age 18 to 21 years ranged from 17.9 to 24.1%. After transitioning to disrupted treatment or no treatment, low percentages of patients returned to pharmacotherapy use (disrupted treatment: 15.7–21.5% per year; no treatment, 2.7–3.8% per year). Across all age groups, statistically significantly greater (p < 0.05) percentages of patients with co-occurring psychiatric disorders used lisdexamfetamine, dextroamphetamine-amphetamine mix short acting, and non-stimulants compared with patients without co-occurring psychiatric disorders. Patients with co-occurring psychiatric disorders remained on ADHD pharmacotherapy longer and switched or augmented their pharmacotherapy more frequently than patients without co-occurring psychiatric comorbidities.ConclusionsPatients rarely reinitiated treatment after pharmacotherapy was disrupted or discontinued, emphasizing the need for increased focus on the management of ADHD as patients transition from adolescence to adulthood.