Pharmacotherapy of Chronic Neuropsychiatric Conditions During Pregnancy.

Many pregnant persons will experience neuropsychiatric conditions during pregnancy, including migraine, attention deficit disorder, depression, and anxiety. Treatment of each of these conditions requires shared decision-making among the individual, family, and health care team. Although medications may include risk, the benefits often outweigh the potential fetal risks. In this article, we review pharmacologic treatment options for each of these conditions and appropriate use in pregnancy to maintain the stability of conditions and to optimize maternal and fetal outcomes.

Theobromine improves hyperactivity, inattention, and working memory via modulation of dopaminergic neural function in the frontal cortex of spontaneously hypertensive rats.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous research indicated that theobromine (TB), a methylxanthine, enhances cognitive function in rodents via the PFC. This study investigates TB's effects on hyperactivity and cognitive function in stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received a diet containing 0.05% TB for 40 days, while control rats received normal diets. Age-matched male Wistar-Kyoto rats (WKY) served as genetic controls. During the TB administration period, we conducted open-field tests and Y-maze tasks to evaluate hyperactivity and cognitive function, then assessed dopamine concentrations and tyrosine hydroxylase (TH), dopamine receptor D1-5 (DRD1-5), dopamine transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), and brain-derived neurotrophic factor (BDNF) expressions in the PFC. Additionally, the binding affinity of TB for the adenosine receptors (ARs) was evaluated. Compared to WKY, SHR exhibited hyperactivity, inattention and working memory deficits. However, chronic TB administration significantly improved these ADHD-like behaviors in SHR. TB administration also normalized dopamine concentrations and expression levels of TH, DRD2, DRD4, SNAP-25, and BDNF in the PFC of SHR. No changes were observed in DRD1, DRD3, DRD5, DAT, and VMAT-2 expression between SHR and WKY rats, and TB intake had minimal effects. TB was found to have affinity binding to ARs. These results indicate that long-term TB supplementation mitigates hyperactivity, inattention and cognitive deficits in SHR by modulating dopaminergic nervous function and BDNF levels in the PFC, representing a potential adjunctive treatment for ADHD.

Adults with both bipolar disorder and ADHD.

ADHD and bipolar disorder (BP) commonly coexist, and both share key symptoms, depending on affective state and emotional dysregulation. The overlap poses diagnostic challenges and may lead to underdiagnoses. Comorbid cases exhibit worsened symptom burden, increased psychiatric morbidity, admissions, and suicide attempts. Treating BP before ADHD is recommended. Stimulant use combined with mood stabilisers may be effective and relatively safe; however, this review finds that well-designed randomised controlled studies in the area is warranted.

Short- and Long-Term Outcomes of Suboptimal Medication Adherence in Adolescents with Attention-Deficit/Hyperactivity Disorder: A Systematic Literature Review.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition with severe and life-long consequences. Adolescents and young adults represent a particularly vulnerable subgroup because of the unique demands of their developmental stage. Despite the well-known efficacy of medication treatment for ADHD, there remains a notable concern regarding poor medication adherence in this population. Objectives: This systematic literature review aimed to synthesize the existing empirical evidence on the outcomes and consequences of medication nonadherence among adolescents and young adults with ADHD. Methods: An extensive database search was conducted on September 26, 2022, with no time limits applied. The databases included Scopus, PubMed, CINAHL, Cochrane, and PsycINFO. Results: Six studies met the inclusion criteria. Each study revealed that medication nonadherence was associated with a range of adverse outcomes, including decreased academic performance, heightened familial, and psychological stress, and an increased likelihood of substance use, pregnancy, obesity, and injury. Conversely, adherence led to improvements in at least one ADHD-related outcome. Conclusions: Research exploring the consequences of suboptimal medication adherence in adolescents and young adults with ADHD is currently limited, and effective strategies to address this issue remain scarce. A thorough understanding of such consequences is critical for developing interventions aimed at improving medication adherence and mitigating the risk of adverse outcomes, especially considering the susceptibility of this population.

Dispensing of attention-deficit hyperactivity disorder medications for adults in Aotearoa New Zealand.

AIM: To report dispensing trends for attention-deficit hyperactivity disorder (ADHD) in Aotearoa New Zealand, focussing on adults in order to highlight increasing demand for ADHD treatment by adults and to prompt discussion. METHOD: Demographic and dispensing data for ADHD were obtained from the Pharmaceutical Collection between the years 2006 and 2022. This was stratified according to child (<18 years) and adult (≥18 years) populations. Population dispensing rates for methylphenidate and atomoxetine were calculated. Key findings are reported to reveal demographic and dispensing trends for medication treated ADHD in Aotearoa New Zealand. RESULTS: More males are dispensed ADHD medication than females, although this is less evident for adults (54.8% male). Maori adults are dispensed ADHD medication at a lower rate (10.1%) than Maori children (22.9%). There was a 10-fold increase in dispensing of ADHD medication for adults compared to a three-fold increase for children over the study period. New dispensing for adults doubled between 2011 and 2022. CONCLUSION: Medication treatment for adult ADHD is increasing in Aotearoa New Zealand and includes treatment for persisting childhood ADHD and new diagnoses made in adulthood. Despite increases, dispensing rates for ADHD remain lower than prevalence estimates, suggesting a significant treatment gap. Addressing the treatment gap for ADHD may reduce negative effects of ADHD, but wider social influences should also be considered.

Long-Term Cardiovascular Risk Associated With Treatment of Attention-Deficit/Hyperactivity Disorder in Adults.

BACKGROUND: Incrementing numbers of patients treated for attention-deficit/hyperactivity disorder (ADHD) call for scrutiny concerning long-term drug-safety. OBJECTIVES: This study aims to investigate associations between long-term use of ADHD treatment and cardiovascular outcomes. METHODS: Using nationwide registers, adult patients first-time initiated on ADHD treatment between 1998 and 2020 were identified. Exposure groups were prior users, <1 defined daily dose (DDD) per day, ≥1 DDD per day determined at start of follow-up, and 1 year after patients' first claimed prescription. Outcomes were acute coronary syndromes, stroke, heart failure, and a composite of the above. RESULTS: At start of follow-up, 26,357, 31,211, and 15,696 individuals were correspondingly categorized as prior users (42% female, median age: 30 years [Q1-Q3: 23-41 years]), <1 DDD per day (47% female, median age: 31 years [Q1-Q3: 24-41 years]), and ≥1 DDD per day (47% female, median age: 33 years [Q1-Q3: 25-41 years]), respectively. Comparing ≥1 DDD per day with prior users, elevated standardized 10-year absolute risk of stroke (2.1% [95% CI: 1.8%-2.4%] vs 1.7% [95% CI: 1.5%-1.9%]), heart failure (1.2% [95% CI: 0.9%-1.4%] vs 0.7% [95% CI: 0.6%-0.8%]), and the composite outcome (3.9% [95% CI: 3.4%-4.3%] vs 3.0% [95% CI: 2.8 %-3.2%]) was found-with corresponding risk ratios of 1.2 (95% CI: 1.0-1.5), 1.7 (95% CI: 1.3-2.2), and 1.3 (95% CI: 1.1-1.5). No apparent associations were found for acute coronary syndrome (1.0% [95% CI: 0.8%-1.2%] vs 0.9% [95% CI: 0.8%-1.0%]). CONCLUSIONS: Possible associations between elevated long-term cardiovascular risk and increasing dosage of ADHD treatment use in a young patient group should warrant further investigation.

A Post-Hoc Analysis of Emotional Lability With Delayed-Release/Extended-Release Methylphenidate in Children Aged 6 to 12 Years of Age Participating in Two Phase 3 Clinical Trials.

OBJECTIVE: DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years. Post hoc analyses of two pivotal Phase 3 trials: HLD200-107 (NCT02493777) and HLD200-108 (NCT02520388) evaluated emotional lability (EL) with DR/ER-MPH treatment. METHODS: Differences in Conners Global Index-Parent (CGI-P) EL subscale scores and age- and gender-adjusted T-scores over an open-label titration phase (HLD200-107) and between treatment and placebo groups at endpoint (HLD200-108) were evaluated. RESULTS: In HLD200-107 (N = 117) mean CGI-P EL subscale scores improved from 5.3 to 1.3 (p < .0001) after 6 weeks; in HLD200-108 significant improvements were observed in the treatment group (n = 81) versus placebo (n = 80; 3.11 vs. 4.08; p = .0053). T-scores showed an improvement with DR/ER-MPH treatment in both trials. Few emotional adverse events (AEs) were reported. CONCLUSION: DR/ER-MPH treatment resulted in statistically significant improvements in EL to the level of non-ADHD peers as contextualized by T-scores.

From Consensus Statement to Pills to Pixels: New Innovations in Attention-Deficit/Hyperactivity Disorder Care.

Objectives: This review aims to present recent innovations and advancements in attention-deficit/hyperactivity disorder (ADHD) care, encompassing international consensus statement, new medication formulations, digital therapeutics, and neurostimulation devices. Methods: A comprehensive literature search of relevant articles published in the past five years was conducted, emphasizing the evidence base, efficacy, safety, and practical implications of these advancements. Results: The World Federation of ADHD Consensus Statement offers an updated diagnostic and treatment framework rooted in global scientific evidence. There are several newer ADHD medication formulations, including a nonstimulant (Viloxazine extended release) and the first transdermal amphetamine patch approved to treat ADHD. These options offer some unique benefits to personalize treatment based on symptom profile, lifestyle, preferences, and response. Digital tools offer additional means to restructure environments for individuals with ADHD, reducing impairment and reliance on others. In addition, digital therapeutics enhance access, affordability, personalization, and feasibility of ADHD care, complementing or augmenting existing interventions. Trigeminal nerve stimulation emerges as a well-tolerated nonpharmacological, device-based treatment for pediatric ADHD, with initial trials indicating effect sizes comparable to nonstimulant medications. Conclusions: These innovations in ADHD care represent clinically significant new treatment options and opportunities for personalized care. Health care professionals should integrate these developments into clinical practice, mindful of individual patient and family needs and preferences. Future research should assess long-term outcomes, cost-effectiveness, and acceptability of these innovations.

Hypokalaemia associated with excessive cola-flavoured drinks consumption.

We present a case involving a male patient in his 30s who was admitted to hospital due to recurrent episodes of hypokalaemia over the past 5 years. His medical history revealed hypertension, attention deficit hyperactivity disorder (ADHD), autism, and paranoia. He was taking citalopram, ramipril, amlodipine, and pramipexole. Tests indicated normal levels of aldosterone/renin ratio and plasma metanephrines. On reviewing his dietary history, it was noted that he consumed 3 to 3.5 L of cola-flavoured drinks on a daily basis. Normal potassium levels were achieved after a significant reduction in cola-flavoured drinks intake and potassium replacement. Subsequent outpatient clinic follow-up revealed that normal potassium levels were maintained even after the patient ceased taking potassium replacement tablets. Given the rarity of hypokalaemia associated with fizzy drinks, the underlying mechanism for this association remains unclear. In this case report, we attempt to provide a possible explanation for the involved mechanisms.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Fetal alcohol spectrum disorder and attention deficit hyperactivity disorder stimulant trial in children: an N-of-1 pilot trial to compare stimulant to placebo (FASST): protocol.

INTRODUCTION: Fetal alcohol spectrum disorder (FASD) is a neurodevelopmental disorder caused by alcohol exposure during pregnancy. FASD is associated with neurodevelopmental deviations, and 50%-94% of children with FASD meet the Diagnostic and Statistical Manual of Mental Disorders-fifth edition diagnostic criteria for attention deficit hyperactivity disorder (ADHD). There is a paucity of evidence around medication efficacy for ADHD symptoms in children with FASD. This series of N-of-1 trials aims to provide pilot data on the feasibility of conducting N-of-1 trials in children with FASD and ADHD. METHODS AND ANALYSIS: A pilot N-of-1 randomised trial design with 20 cycles of stimulant and placebo (four cycles of 2-week duration) for each child will be conducted (n=20) in Melbourne, Australia.Feasibility and tolerability will be assessed using recruitment and retention rates, protocol adherence, adverse events and parent ratings of side effects. Each child's treatment effect will be determined by analysing teacher ADHD ratings across stimulant and placebo conditions (Wilcoxon rank). N-of-1 data will be aggregated to provide an estimate of the cohort treatment effect as well as individual-level treatment effects. We will assess the sample size and number of cycles required for a future trial. Potential mediating factors will be explored to identify variables that might be associated with treatment response variability. ETHICS AND DISSEMINATION: The study was approved by the Hospital and Health Service Human Research Ethics Committee (HREC/74678/MonH-2021-269029), Monash (protocol V6, 25 June 2023).Individual outcome data will be summarised and provided to participating carers and practitioners to enhance care. Group-level findings will be presented at a local workshop to engage stakeholders. Findings will be presented at national and international conferences and published in peer-reviewed journals. All results will be reported so that they can be used to inform prior information for future trials. TRIAL REGISTRATION NUMBER: NCT04968522.

Switch to Lisdexamfetamine in the Treatment of Attention-Deficit Disorder at a Psychiatric Outpatient Clinic for School-Aged Children: A Danish Cohort Study.

Objectives: This study aimed to examine switch from first-line methylphenidate (MPH) to lisdexamfetamine (LDX) in school-aged children with attention-deficit/hyperactivity disorder (ADHD). Methods: This is a retrospective observational study based on systematic review of patient records of all children (7-13 years) diagnosed with ADHD and referred to a Danish specialized outpatient clinic. The study included 394 children switching from MPH to LDX as either second-line or third-line treatment (atomoxetine [ATX] as second-line treatment) during the study period from April 1, 2013, to November 5, 2019. Results: One in five children switched from MPH to LDX at some point during the study period. The most frequent reasons for switching to LDX were adverse effects (AEs; 70.0% for MPH, 68.3% for ATX) and lack of efficiency (52.0% for MPH, 72.7% for ATX). Top five AEs of LDX were decreased appetite (62.4%), insomnia (28.7%), irritability/aggression (26.1%), weight decrease (21.1%), and mood swings (13.9%). MPH and LDX had similar AE profiles, yet most AEs were less frequent after switching to LDX. At the end of the study period, the majority were prescribed LDX as second-line rather than third-line treatment (86.1% in 2019). However, the likelihood of LDX as second-line treatment decreased with the number of psychiatric comorbidities, ADHD symptom severity as assessed by parents, and if AEs were a reason for MPH discontinuation. Among children observed for at least 1 year after initiation of LDX, 41.3% continued LDX treatment for a year or longer. LDX continuation was less likely if AEs were a reason for MPH discontinuation. Similarly to MPH and ATX, the most frequent reasons for LDX discontinuation were AEs (74.4%) and lack of efficiency (34.7%). Implications: The findings support LDX as an important option in the personalized treatment of children with ADHD and may support prescribers in the clinical decision-making on switching medication.

Costs associated with adverse events during treatment episodes for adult attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) medication is frequently associated with adverse events (AEs), but limited real-world data exist regarding their costs from a payer's perspective. Therefore, this study evaluated the healthcare costs associated with common AEs among adult patients treated for ADHD in the US. METHODS: Eligible adults treated for ADHD were identified from a large US claims database (1 October 2015-30 September 2021). A retrospective cohort study design was used to assess excess healthcare costs and costs directly related to AE-specific claims per-patient-per-month (PPPM) associated with 10 selected AEs during ADHD treatment. To account for all costs associated with the AE, treatment episodes with a given AE were compared to similar treatment episodes without this AE. Entropy balancing was used to create cohorts with similar characteristics. Studied AEs were selected based on their prevalence in clinical trials for common ADHD medications and were identified from ICD-10-CM diagnosis codes recorded in claims. RESULTS: Among the 461,464 patients included (mean age: 34.2 years; 45.5% males), 49.4% had ≥1 AE during their treatment episode. Treatment episodes with AEs were associated with statistically significant AE-specific medical costs (erectile dysfunction: $57; fatigue: $82; dry mouth: $90; diarrhea: $162; insomnia: $147; anxiety: $281; nausea: $299; constipation: $356; urinary hesitation: $491; feeling jittery: $723) and excess healthcare costs PPPM (erectile dysfunction: $120, fatigue: $248, insomnia: $265, anxiety: $380, diarrhea: $441, dry mouth: $485, nausea: $709, constipation: $802, urinary hesitation: $1,105, feeling jittery: $1,160; p < .05). LIMITATIONS: AEs were identified based on recorded diagnosis on medical claims and likely represent more severe AEs. Therefore, costs may not be representative of milder AEs. CONCLUSIONS: This study found that AEs occurring during ADHD treatment episodes are associated with significant healthcare costs. This highlights the potential of treatments with favorable safety profiles to alleviate the burden experienced by patients and the healthcare system.

A critical review of the dextroamphetamine transdermal system for the treatment of ADHD in adults and pediatric patients.

INTRODUCTION: The dextroamphetamine transdermal system (d-ATS) is a stimulant patch recently approved by the United States (U.S.) Food and Drug Administration for the treatment of attention-deficit/hyperactivity disorder (ADHD). AREAS COVERED: The composition of the d-ATS, pharmacokinetics, and metabolism are presented along with data from dermal trials evaluating the tolerability of patch application at various skin sites. Efficacy and safety data from a laboratory classroom study in children and adolescents including effect sizes are assessed. Pharmacokinetic-pharmacodynamic modeling of variable wear times is also discussed. EXPERT OPINION: Although stimulants are recommended as first-line treatment for ADHD in the U.S. some patients may have difficulty swallowing intact tablets and capsules, or dislike the taste or texture of chewable, oral disintegrating, or liquid formulations. The d-ATS fills an unmet need for those with ADHD who are unable or prefer not to take medication orally. Varying wear time of the d-ATS also gives flexibility in length of stimulant effect which may be useful for patients with changing schedules. However, dermal discomfort must be considered in addition to the usual amphetamine side effects when prescribing the d-ATS. Patient and provider experience will determine how frequent the use of d-ATS becomes.

Understanding health behaviors that modify the risk for obesity in ADHD.

OBJECTIVE: Research provides support for the associated risk of inadequate sleep duration, limited physical activity, and excessive media use in attention-deficit/hyperactivity disorder (ADHD) and obesity. The present study aims to (1) examine the association between ADHD and overweight or obese status (OW/OB); (2) comprehensively examine sleep duration, physical activity, and media use as potential moderators of OW/OB; and (3) examine the moderating effects of these health behaviors cross-sectionally by comparing medicated youth with ADHD, unmedicated youth with ADHD, and youth without ADHD. METHODS: Data were acquired from the 2018 and 2019 National Survey of Children's Health, a nationally representative survey of caregivers conducted across the United States. The current study used data for youth 11-17 years old with a final sample size of 26,644. Hours of sleep, physical activity, and media use per day were dichotomized based on national recommendation guidelines for each health behavior (i.e., either meeting or not meeting guidelines). RESULTS: The OW/OB prevalence rate was 7% greater among unmedicated youth with ADHD than among medicated youth with ADHD. Medicated youth with ADHD and peers without ADHD had similar OW/OB rates. Among medicated youth with ADHD, physical activity, sleep duration, and media use did not contribute to OW/OB risk after controlling for family poverty level. However, among unmedicated youth with ADHD, meeting sleep duration guidelines was linked to a lower OW/OB risk. CONCLUSION: Overall, findings suggest that clinical providers and parents may wish to prioritize improved sleep duration in the management of OW/OB risk in youth with ADHD.