Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

The Use of Methylphenidate During Inpatient Rehabilitation After Pediatric Traumatic Brain Injury: Population Characteristics and Prescribing Patterns.

OBJECTIVE: To understand how methylphenidate (MPH) is used in youth with traumatic brain injury (TBI) during inpatient pediatric rehabilitation. SETTING: Inpatient pediatric rehabilitation. PARTICIPANTS: In total, 234 children with TBI; 62 of whom received MPH and 172 who did not. Patients were on average 11.6 years of age (range, 2 months to 21 years); 88 of 234 were female; the most common mechanism of injury was motor vehicle collision (49%); median (IQR) acute hospital length of stay (LOS) and inpatient rehabilitation LOS were 16 (10-29) and 23 (14-39), respectively; 51 of 234 were in a disorder of consciousness cognitive state at time of inpatient rehabilitation admission. DESIGN: Multicenter, retrospective medical record review. MAIN MEASURES: Patient demographic data, time to inpatient pediatric rehabilitation admission (TTA), cognitive state, MPH dosing (mg/kg/day). RESULTS: Patients who received MPH were older (P = .011); TTA was significantly longer in patients who received MPH than those who did not (P =.002). The lowest recorded dose range by weight was 0.05 to 0.89 mg/kg/d, representing an 18-fold difference; the weight-based range for the maximum dose was 0.11 to 0.97 mg/kg/d, a 9-fold difference. Patients in lower cognitive states at admission (P = .001) and at discharge (P = .030) were more likely to receive MPH. Five patients had side effects known to be associated with MPH; no serious adverse events were reported. CONCLUSION: This multicenter study indicates that there is variable use of MPH during acute inpatient rehabilitation for children with TBI. Children who receive MPH tend to be older with lower cognitive states. Dosing practices are likely consistent with underdosing. Clinical indications for MPH use during inpatient pediatric rehabilitation should be better defined. The use of MPH, as well as its combination with other medications and treatments, during inpatient rehabilitation needs to be further explored.

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.

Brain connectivity changes to fast versus slow dopamine increases.

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, pspin < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r(19) = -0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Improving Methylphenidate Titration in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): A Randomized Controlled Trial Using Placebo-Controlled Titration Implemented in Clinical Practice.

BACKGROUND AND OBJECTIVES: Concerns exist regarding the rising use of methylphenidate. A double-blind, placebo-controlled methylphenidate titration (PCT) for children with attention-deficit/hyperactivity disorder (ADHD) has shown potential to improve titration (i.e., detection of placebo responders and larger ADHD symptom improvement) in experimental settings. This study aims to determine if these advantages can be transferred to clinical settings. METHOD: Children (aged 5-13 years) with an ADHD diagnosis and an indication to start methylphenidate (MPH) treatment were recruited. Participants were randomized to PCT or care as usual (CAU) in a 1:1 ratio followed by a 7-week randomized controlled trial (T1) and 6-month, naturalistic, open-label follow-up (T2). Parents, teachers, and physicians rated ADHD symptoms, ADHD medication use, MPH dosing, and treatment satisfaction using questionnaires. RESULTS: A total of 100 children were enrolled and randomized to PCT (n = 49) or CAU (n = 51). In the PCT group, we found 8.2% placebo responders, 16.3% non-responders, and 65.3% responders to MPH. With PCT compared with CAU, a significantly larger number of children discontinued MPH (T1: 24.5 vs 5.9%, p = 0.009; T2: 41.7 vs 10.4%, p < 0.001) and refrained from using other pharmacological treatment (T1: 20.4 vs 3.9%, p = 0.013; T2: 20.83 vs 6.25%, p = 0.002). At both timepoints, there were no significant differences between the groups in the average dose of MPH, ADHD symptoms, or treatment satisfaction. CONCLUSIONS: PCT can be used to improve detection of children who do not benefit from MPH, and may therefore potentially reduce overtreatment of ADHD with MPH.

Delayed-onset posttraumatic stress disorder with response to methylphenidate / Trastorno por estrés postraumático de expresión retardada con respuesta a metilfenidato

Introduction: Posttraumatic stress disorder (PTSD) is extremely frequent in war veterans and has been widely studied. However, the efficacy of currently available pharmacological and psychotherapeutic treatments of war PTSD and other causes of PTSD is very limited. Method We present a case of war PTSD with delayed expression, with a good response to complementation with methylphenidate after a failed treatment with venlafaxine and risperidone. Results We review the role of dopamine in the pathophysiology of PTSD and the scarce studies in the treatment of PTSD with dopaminergic drugs that show an improvement in re-experimentation and in affective symptoms, especially anhedonia and cognitive impairment. Conclusions We conclude that the use of methylphenidate and other dopaminergic drugs can be a promising treatment for PTSD, a high prevalent disease with a high resistance to treatment, for which we encourage the use of large sample studies. (AU)

Introducción: El trastorno por estrés postraumático (TEPT) es extremadamente prevalente en veteranos de guerra y ha sido ampliamente estudiado. Sin embargo, la eficacia de los tratamientos farmacológicos y psicoterapéuticos disponibles es aún muy limitada, tanto en el TEPT de guerra como en el TEPT por otras causas. Método Presentamos un caso de TEPT de guerra con expresión retardada, con una buena respuesta al metilfenidato a su tratamiento con venlafaxina y risperidona, que había resultado ineficaz. Resultados Revisamos el rol de la dopamina en la psicopatología del TEPT y los pocos estudios del tratamiento del TEPT con fármacos dopaminérgicos, en los que se muestra una mejoría en los síntomas de reexperimentación y los síntomas afectivos, especialmente la anhedonia y los déficits cognitivos secundarios. Conclusiones Consideramos que el uso del metilfenidato y de otros fármacos dopaminérgicos podrían ser prometedores el tratamiento del TEPT, un trastorno altamente prevalente y con alta resistencia al tratamiento habitual. Por esto, animamos a realizar estudios con muestras amplias. (AU)

Estimulantes de tipo anfetamínico en estudiantes de medicina latinoamericanos: una revisión / Amphetamine-type stimulants in Latin American medicine students: a review

Introducción: el consumo de estimulantes de tipo anfetamínico (ETA) y sus derivados está cada vez más presente en los estudiantes universitarios y, en particular, en los programas de medicina. El objetivo principal de este estudio fue revisar la literatura sobre el uso de ETA y sus derivados en estudiantes de medicina latinoamericanos. Materiales y método: se realizó una revisión de la literatura disponible, utilizando las bases de datos PubMed, SciELO y LILACS. Se encontraron un total de 1.054 artículos, de los cuales 17 fueron seleccionados para esta revisión. Resultados: la revisión muestra, en general, una mayor frecuencia de uso de ETA en estudiantes de medicina de América Latina en comparación con la población general y estudiantes de otras carreras universitarias. También existe una tendencia a un mayor uso en hombres, de mayor nivel socioeconómico y en cursos posteriores del programa. La razón más informada para usar ETA fue aumentar el rendimiento académico. Como factor protector se destacaron los deportes, el tiempo en familia y la profesión de alguna creencia religiosa. De los artículos seleccionados, no se encontraron estudios sobre las consecuencias a largo plazo del uso de ETA en estudiantes de medicina. Discusión: en resumen, los estudiantes de medicina latinoamericanos tienen un alto consumo de ETA, por lo que es evidente la necesidad de nuevos estudios para mejorar la precisión estadística, determinar factores de riesgo específicos, estudiar las consecuencias a largo plazo y establecer políticas de prevención y tratamiento.

Introduction: the consumption of amphetamine-type stimulants (ATS) and their derivatives are increasingly present in university students and in particular in medical programs. The main objective of this study was to review the literature on the use of ATS and their derivatives in Latin American medical students. Materials and method: a review of the literature available was performed, using PubMed, SciELO, and LILACS databases. A total of 1054 articles were found, of which 17 were selected for this review. Results: the review generally shows a higher frequency of use of ATS in medical students of Latin America compared to the general population and students from other university degrees. There is also a tendency of a higher use in men, from higher socioeconomic status, and in later courses of the program. The most reported reason for using ATS was to increase the academic performance. As a protective factor, sports, family time and professing some religious belief stood out. Of the selected articles, no studies were found on the long-term consequences of the use of ATS in medical students. Discussion: in summary, Latin American medical students have a high consumption of ATS, and therefore there is an evident need for new studies to improve statistical precision, to determine specific risk factors, to study long-term consequences, and to stablish prevention policies and treatment.

Methylphenidate and Other Pharmacologic Treatments for Apathy in Alzheimer's Disease.

Apathy is a common and important yet often ignored neuropsychiatric symptom of Alzheimer's disease (AD). Cholinesterase inhibitors and memantine, used to treat AD, appear ineffective against apathy. A meta-analysis of 4 randomized, placebo-controlled trials (RCTs) found that psychostimulants significantly attenuated apathy ratings in AD. However, the pooled sample size in this meta-analysis was just 156, and one of the trials was a 2-week crossover study with a large effect. A large RCT (n = 200) has now been published. This study found that methylphenidate (MPH; 20 mg/d) was superior to placebo in the attenuation of apathy scores in patients with possible or probable, mild to moderate AD; the advantage was evident by the end of the second month of treatment and remained evident to the end of 6 months. The effect size at 6 months was small (Cohen d = 0.37). In this RCT, disappointingly, MPH was not superior to placebo on secondary outcomes, including informant-rated apathy, dependence, activities of daily living, quality of life, and neurocognitive performance; caregiver burden was not formally studied. Speculatively, the psychosocial intervention provided to all participants in this RCT may have boosted response in the placebo group, thereby attenuating differences in outcomes between the MPH and placebo groups. A reasonable conclusion is that whereas MPH may attenuate the severity of apathy in patients with AD across as long as 6 months, the absence of improvements in measures of dependence, activities of daily living, and quality of life suggest that this effect of MPH on apathy may not be clinically significant. An unanswered question is whether the benefits of MPH may be clinically significant in real world practice settings in which the delivery of behavioral interventions is not feasible.

Chronic treatment and abstinence from methylphenidate exposure dose-dependently changes glucose metabolism in the rat brain.

Methylphenidate (MP) is extensively prescribed for attention deficit hyperactivity disorder (ADHD). While MP is effective in ameliorating symptoms of ADHD, MP is also used illicitly among healthy subjects without ADHD for cognitive-enhancing purposes. The deleterious consequences associated with long-term MP use as well as its cessation on brain activity remains to be understood. To address this, we administered either water, low dose MP (LD MP), or high dose MP (HD MP) to healthy adolescent Sprague Dawley rats, with five days on the treatment and two days off for thirteen consecutive weeks. Rats were then abstinent from their respective treatments for four weeks. Using positron emission tomography (PET) and fluorodeoxyglucose [18F] (FDG), we scanned rats at three time points: after thirteen weeks of treatment, after one week of abstinence, and after four weeks of abstinence. After thirteen weeks of LD and HD MP treatment, increases in brain glucose metabolism (BGluM) were seen in several cortical and subcortical regions associated with sensory and motor functions as well as learning and memory. One-week abstinence from LD MP treatment promoted increased BGluM compared to both water treated and HP MP treated groups. After four weeks of abstinence, little group differences were seen. Longitudinally, we observed contrasting differences on BGluM depending on whether a LD or HD of MP was administered. Our results demonstrate that MP treatment during adolescence can significantly alter BGluM. Moreover, these changes in brain activity do not subside in many areas of the brain after both one and four-week drug abstinence.

Internet parent-child interaction therapy (I-PCIT) in medically ill child: A case report.

INTRODUCTION: This case illustrates the feasibility, benefit, and putative enhanced ecological validity of performing internet-parent-child interaction therapy (I-PCIT) in the parent-child dyad's home for the treatment of behavior problems in medically ill children in the context of a global pandemic. PATIENT CONCERNS: Parents of a 5-year-old girl initially presented with concerns regarding inattentiveness, physical and verbal fighting with her siblings, and getting kicked out of daycare for hitting another child. Patient also had difficulties sleeping at night. DIAGNOSES: Patient was diagnosed with electrical status epilepticus in sleep, frontal lobe executive function deficit, and attention deficit hyperactivity disorder. INTERVENTIONS: Patient received a course of I-PCIT. Equipment included a cell phone with video capabilities connected to a videotelephony software program and set-up in the child's home by the parents. The treatment course included 8, 1-hour, weekly teaching/coaching sessions (7 of which were performed using I-PCIT) plus 1 follow-up booster session 6 months later. OUTCOMES: Home-based I-PCIT implementation greatly improved disruptive behaviors in a young child with electrical status epilepticus in sleep and attention deficit hyperactivity disorder. CONCLUSION: A combination of I-PCIT and methylphenidate allowed her to be successful at home and in a school setting. More research is needed on PCIT adaptations, such as home-based and internet-based PCIT, for medically ill children as well as treatment protocols for combined therapies.

Dopaminergic and noradrenergic modulation of stress-induced alterations in brain activation associated with goal-directed behaviour.

BACKGROUND: Acute stress is thought to reduce goal-directed behaviour, an effect purportedly associated with stress-induced release of catecholamines. In contrast, experimentally increased systemic catecholamine levels have been shown to increase goal-directed behaviour. Whether experimentally increased catecholamine function can modulate stress-induced reductions in goal-directed behaviour and its neural substrates, is currently unknown. AIM: To assess whether and how experimentally induced increases in dopamine and noradrenaline contribute to the acute stress effects on goal-directed behaviour and associated brain activation. METHODS: One hundred participants underwent a stress induction protocol (Maastricht acute stress test; MAST) or a control procedure and received methylphenidate (MPH) (40 mg, oral) or placebo according to a 2 × 2 between-subjects design. In a well-established instrumental learning paradigm, participants learnt stimulus-response-outcome associations, after which rewards were selectively devalued. Participants' brain activation and associated goal-directed behaviour were assessed in a magnetic resonance imaging scanner at peak cortisol/MPH concentrations. RESULTS: The MAST and MPH increased physiological measures of stress (salivary cortisol and blood pressure), but only MAST increased subjective measures of stress. MPH modulated stress effects on activation of brain areas associated with goal-directed behaviour, including insula, putamen, amygdala, medial prefrontal cortex, frontal pole and orbitofrontal cortex. However, MPH did not modulate the tendency of stress to induce a reduction in goal-directed behaviour. CONCLUSION: Our neuroimaging data suggest that MPH-induced increases in dopamine and noradrenaline reverse stress-induced changes in key brain regions associated with goal-directed behaviour, while behavioural effects were absent. These effects may be relevant for preventing stress-induced maladaptive behaviour like in addiction or binge eating disorder.

Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward.

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).

MicroPET/CT assessment of neurochemical effects in the brain after long-term methylphenidate treatment in nonhuman primates.

Methylphenidate (MPH) is a psychostimulant approved by the FDA to treatment Attention-Deficit Hyperactivity Disorder (ADHD). MPH is believed to exert its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. We used a quantitative non-invasive PET imaging technique to study the effects of long-term methylphenidate use on the central nervous system (CNS). We conducted microPET/CT scans on young adult male rhesus monkeys to monitor changes in the dopaminergic system. We used [18F] AV-133, a ligand for the vesicular monoamine transporter 2 (VMAT2), and [18F]FESP a ligand for the D2 and 5HT2 receptors. In this study we evaluated the effects if chronic MPH treatment in the nonhuman primates (NHP). Two-year-old, male rhesus monkeys were orally administered MPH diluted in the electrolyte replenisher, Prang, twice a day, five days per week (M-F) over an 8-year period. The dose of MPH was gradually escalated from 0.15 mg/kg initially to 2.5 mg/kg/dose for the low dose group, and 1.5 mg/kg to 12.5 mg/kg/dose for the high dose group (Rodriguez et al., 2010). Scans were performed on Mondays, about 60 h after their last treatment, to avoid the acute effects of MPH. Tracers were injected intravenously ten minutes before microPET/CT scanning. Sessions lasted about 120 min. The Logan reference tissue model was used to determine the Binding Potential (BP) of each tracer in the striatum with the cerebellar cortex time activity curve as an input function. Both MP treatment groups had a lower [18F] AV-133 BP, although this failed to reach statistical significance. MPH treatment did not have a significant effect on The BP of [18F] FESP in the striatum. Long-term administration of MPH did not significant change any of the marker of monoamine function used here. These data suggest that, despite lingering concerns, long-term use of methylphenidate does not negatively impact monoamine function. This study also demonstrates that microPET imaging can distinguish differences in binding potentials of a variety of radiotracers in the CNS of NHPs. This approach may provide minimally-invasive biomarkers of neurochemical processes associated with chronic exposure to CNS medications. (Supported by NCTR).

Fluoxetine Potentiates Oral Methylphenidate-Induced Gene Regulation in the Rat Striatum.

Methylphenidate (MP) is combined with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) to treat various disorders. MP, a dopamine reuptake inhibitor, helps manage attention-deficit hyperactivity disorder (ADHD) and is abused as a cognitive enhancer; it has a reduced addiction liability. We showed that combining FLX (serotonin) with MP potentiates MP-induced gene regulation in the striatum. These studies used intraperitoneal drug administration, which is relevant for MP abuse. Clinically, MP and FLX are taken orally (slower bioavailability). Here, we investigated whether chronic oral administration of MP and FLX also altered striatal gene regulation. MP (30/60 mg/kg/day), FLX (20 mg/kg/day), and MP + FLX were administered in rats' drinking water for 8 h/day over 4 weeks. We assessed the expression of dynorphin and substance P (both markers for striatal direct pathway neurons) and enkephalin (indirect pathway) by in situ hybridization histochemistry. Chronic oral MP alone produced a tendency for increased dynorphin and substance P expression and no changes in enkephalin expression. Oral FLX alone did not increase gene expression. In contrast, when given together, FLX greatly enhanced MP-induced expression of dynorphin and substance P and to a lesser degree enkephalin. Thus, FLX potentiated oral MP-induced gene regulation predominantly in direct pathway neurons, mimicking cocaine effects. The three functional domains of the striatum were differentially affected. MP + SSRI concomitant therapies are indicated in ADHD/depression comorbidity and co-exposure occurs with MP misuse as a cognitive enhancer by patients on SSRIs. Our findings indicate that MP + SSRI combinations, even given orally, may enhance addiction-related gene regulation.

Treatment with Methylphenidate for Attention Deficit Hyperactivity Disorder (ADHD) and the Risk of All-Cause Poisoning in Children and Adolescents: A Self-Controlled Case Series Study.

BACKGROUND: Children and adolescents with attention deficit hyperactivity disorder (ADHD) are at higher risk of all-cause poisoning by drugs and chemicals (intentional or accidental). Currently, there is limited data on whether medication treatment for ADHD can reduce the risk of all-cause poisoning. METHODS: Patients aged 5-18 years with a methylphenidate (MPH) prescription and an incident poisoning diagnosis between January 2001 and June 2020 were identified from the Hong Kong Clinical Data Analysis and Reporting System. A self-controlled case series study design was used to compare the incidence rate ratios (IRRs) of all-cause poisoning during different risk windows (30 days before the first MPH prescription, exposure periods within 30 days of the first prescription, and periods of subsequent exposure) compared with the reference window (other non-exposure periods). RESULTS: 42,203 patients were prescribed ADHD medication in Hong Kong during the study period. Of these, 417 patients who had both an MPH prescription and poisoning incident recorded were included in the main analysis. Compared with other non-exposed periods, a higher risk of poisoning was found in the 30 days before the first prescription (IRR 2.64, 95% confidence interval [CI] 1.33-5.22) and exposure periods within 30 days of the first prescription (IRR 2.18, 95% CI 1.06-4.48), but not during prolonged exposure. However, compared with 30 days before the first prescription as well as exposure periods within 30 days of the first prescription, there was a lower risk during the subsequent exposure (IRRs 0.49 and 0.60, respectively). Similar results to the main analysis were also found in the subgroup analysis of intentional poisoning and females, but not in that of accidental poisoning and males. CONCLUSIONS: The risk of all-cause poisoning was higher shortly before and after the first MPH prescription and became lower during the subsequent prescription period. Our results do not support an association between the use of MPH and an increased risk of all-cause poisoning in children and adolescents and, in fact, suggest that longer-term use of MPH may be associated with a lower risk of all-cause poisoning, although this latter finding requires further study.

Symptomatic and Functional Response and Remission From the Open-Label Treatment-Optimization Phase of a Study With DR/ER-MPH in Children With ADHD.

Objective: Delayed-release and extended-release methylphenidate (DR/ER-MPH), the first stimulant predicted to be absorbed primarily in the colon, demonstrated significant improvements in attention-deficit/hyperactivity disorder (ADHD) symptoms and functional impairment from awakening until evening versus placebo in clinical trials. The clinical significance of these improvements was explored post hoc by examining response and remission thresholds as well as safety in the context of dose optimization.Methods: Data from the open-label, treatment-optimization phase of a phase 3 study of DR/ER-MPH in children (aged 6-12 years) with ADHD, as diagnosed by DSM-5 criteria and enrolled between July 2015 and March 2016, were analyzed. Thresholds for response (anchored to Clinical Global Impressions-Improvement scale [CGI-I] score of 1 or 2) and remission were applied to ADHD Rating Scale-IV (ADHD-RS-IV), Before School Functioning Questionnaire (BSFQ), and Parent Rating of Evening and Morning Behavior, Revised, Morning Subscale (PREMB-R AM) and Evening Subscale (PREMB-R PM) scores. Rates of response, remission, and treatment-emergent adverse events by starting dose were examined.Results: Mean DR/ER-MPH dose increased from 29.7 mg/d at baseline (51% on 20 mg/d; 49% on 40 mg/d) to 66.2 mg/d at week 6. At week 6, most participants achieved response/remission thresholds (response/remission: ADHD-RS-IV: 97%/89%; BSFQ: 98%/94%; PREMB-R AM: 94%/98%; PREMB-R PM: 91%/84%). More participants starting on a 40-mg versus 20-mg dose achieved thresholds at week 1 (P < .02). Weekly treatment-emergent adverse event rates over the open-label period were similar between starting doses.Conclusions: When DR/ER-MPH dosing was optimized for ADHD symptom control throughout the day, the majority of participants achieved thresholds indicating all-day control of ADHD symptoms and functional impairment to the level of their non-ADHD peers.Trial Registration: Data used in this post hoc analysis came from the study with ClinicalTrials.gov identifier: NCT02493777.

Effect of a Multi-Layer, Extended-Release Methylphenidate Formulation (PRC-063) on Sleep in Adults with ADHD: A Randomized, Double-Blind, Forced-Dose, Placebo-Controlled Trial Followed by a 6-month Open-Label Extension.

BACKGROUND: The effects of stimulant treatment on sleep in adults with attention-deficit/hyperactivity disorder (ADHD) are complex and varied, with some individuals experiencing worsening of sleep but others experiencing improvement. METHODS: Data from previously reported trials of the clinical efficacy and safety of the long-acting methylphenidate formulation PRC-063 (Adhansia XR® in the USA; Foquest® in Canada) in adults with ADHD were used to evaluate patient-reported sleep outcomes, as captured using the Pittsburgh Sleep Quality Index (PSQI) and adverse events of insomnia. The trials comprised 4 weeks of randomized, forced-dose PRC-063 treatment at a dose of 0 (placebo), 25, 45, 70, or 100 mg/day followed by an optional 6 months of open-label PRC-063 treatment at an individually optimized dose of 25-100 mg/day. RESULTS: At the end of double-blind treatment, PRC-063 (all doses combined; N = 297) showed no significant difference versus placebo (N = 78) in least squares mean change in global PSQI score from baseline (- 0.7 vs. - 1.3; P = 0.0972) or in scores for each of the seven subscales of the PSQI. For patients enrolled in the open-label extension (N = 184), mean ± standard deviation global PSQI score improved from 7.8 ± 3.55 at the end of double-blind treatment to 5.8 ± 3.11 at 1 month and 5.4 ± 3.21 at 6 months (P < 0.0001). A greater proportion of patients were good sleepers (global PSQI score ≤ 5) at the end of the open-label extension (57.3%) than at baseline (20.9%) or at the end of double-blind treatment (26.0%). In a logistic regression analysis, baseline global PSQI score (odds ratio 1.491; P < 0.0001), but not randomized study treatment (P = 0.1428), was a significant predictor of poor sleep (global PSQI score > 5) at the end of double-blind treatment. Adverse event rates for insomnia (15.8 vs. 3.8%) and initial insomnia (6.1 vs. 1.3%) during double-blind treatment were higher for PRC-063 (all doses combined) than for placebo. Two patients receiving PRC-063 in the double-blind study and one patient in the open-label study were withdrawn because of insomnia adverse events. CONCLUSIONS: Our findings indicate that, on average, PRC-063 had no significant impact on overall sleep quality in adults with ADHD. Although insomnia was observed as an adverse event, when sleep was measured over time as an outcome in its own right for patients receiving dose-optimized PRC-063 open-label, more patients showed improvement in sleep than deterioration. CLINICALTRIALS. GOV IDENTIFER: NCT02139124 and NCT02168127.

The Use of Methylphenidate for Cognitive Enhancement in Young Healthy Adults: The Clinical and Ethical Debates.

OBJECTIVE: Methylphenidate (MP), a drug of choice for attention-deficit/hyperactivity disorder (ADHD), is a federally restricted substance CII in the United States because of abuse and dependence, and similar restrictions are practiced in Canada and around the world. This designation is given to drugs with medical value that present a high potential for abuse. In view of these severe restrictions, it is concerning to find out that a large group of healthy young adults, at least as large as the ADHD group of patients, take MP for cognitive enhancement, in an attempt to improve their academic achievements during studies and examinations. These young adults buy MP illegally and consume it without any medical supervision. The objective of the present debate piece is to present the ethical and clinical issues that need to be addressed in an attempt to solve this dilemma. METHODS: The issues presented here are systematically reviewed and discussed along the following lines: MP effectiveness in enhancing cognitive achievements in healthy people; "As these are normal healthy people, what is the duty of physicians to 'treat' them?"; potential benefits of cognitive enhancement to healthy people; the risks of MP; "How do these young people get their MP?"; and "What can be done?" RESULTS: Methylphenidate is widely used for cognitive enhancement without medical supervision. The effectiveness of MP for cognitive enhancement is well documented along a dose-response curve. Congruent with the results of the randomized trials, repeated studies based on interviews suggest that numerous young people report that cognitive enhancement helps them in improving their academic achievements, and hence also improve their feeling of well-being. Presently, most regulatory and medical organizations limit the use of MP to ADHD and narcolepsy. Yet, the American Academy of Neurology ruled that there is a moral, ethical, and legal basis to prescribe the drug for cognitive enhancement. The drug has known dose-dependent adverse effects that can have serious ramifications and may often lead to poor adherence. The relative risk of MP causing sudden death/arrhythmia is 1.46 (95% confidence interval, 1.03-2.07), and there are estimated 20 million college and university students in the United States in 2020. The rate of sudden death/arrhythmias in this age group ranges between 1 and 10 per 100,000. This translates to an excess of 146 deaths caused by MP every year in the United States considering postsecondary students only. DISCUSSION: We propose that an ethical-clinical debate should be followed by an action plan to ensure that the present reality of millions of young people taking unsupervised MP is not accepted as a force majeure that cannot be changed.