Reduced striatal brain volumes in non-medicated adult ADHD patients with comorbid cocaine dependence

Background

Adult attention deficit/hyperactivity disorder (ADHD) is highly comorbid with other psychiatric disorders, including substance use disorders (SUD). Patients with ADHD and SUD comorbidity respond less well to pharmacological treatment (e.g., methylphenidate), have more severe ADHD symptoms, and are generally more impulsive than ADHD patients without SUD. However, little is known about structural brain abnormalities that may differentiate ADHD patients with and without comorbid SUD.

Methods

We compared regional grey matter volumes of 10 non-medicated male ADHD patients with comorbid cocaine dependence, 14 non-medicated male ADHD patients without cocaine dependence and 15 healthy control participants matched for age and premorbid intellectual functioning, using voxel-based morphometry (VBM) using both a whole-brain analysis and a priori ROI analysis based on the existing ADHD VBM literature.

Results

In a whole brain analysis, ADHD patients with and without cocaine dependence showed smaller volumes in the right putamen and cerebellum compared to healthy controls. In addition, ADHD patients without cocaine dependence showed larger volumes in the midbrain and in the precentral gyrus compared to healthy control participants and larger volumes in the occipital cortex compared to ADHD patients with comorbid cocaine dependence. A direct comparison using the a priori defined ROI approach showed that ADHD patients with cocaine dependence had smaller putamen volumes than ADHD patients without cocaine dependence.

Conclusions

ADHD patients with cocaine dependence show more profound grey matter volume reductions in the striatum compared to ADHD patients without cocaine dependence. Possible implications for treatment are discussed.     

Brain alterations in adult ADHD: Effects of gender,treatment and comorbid depression

Children with attention-deficit/hyperactivity disorder (ADHD) have smaller volumes of total brain matter and subcortical regions, but it is unclear whether these represent delayed maturation or persist into adulthood. We performed a structural MRI study in 119 adult ADHD patients and 107 controls and investigated total gray and white matter and volumes of accumbens, caudate, globus pallidus, putamen, thalamus, amygdala and hippocampus. Additionally, we investigated effects of gender, stimulant treatment and history of major depression (MDD). There was no main effect of ADHD on the volumetric measures, nor was any effect observed in a secondary voxel-based morphometry (VBM) analysis of the entire brain. However, in the volumetric analysis a significant gender by diagnosis interaction was found for caudate volume. Male patients showed reduced right caudate volume compared to male controls, and caudate volume correlated with hyperactive/impulsive symptoms. Furthermore, patients using stimulant treatment had a smaller right hippocampus volume compared to medication-naïve patients and controls. ADHD patients with previous MDD showed smaller hippocampus volume compared to ADHD patients with no MDD. While these data were obtained in a cross-sectional sample and need to be replicated in a longitudinal study, the findings suggest that developmental brain differences in ADHD largely normalize in adulthood. Reduced caudate volume in male patients may point to distinct neurobiological deficits underlying ADHD in the two genders. Smaller hippocampus volume in ADHD patients with previous MDD is consistent with neurobiological alterations observed in MDD.     

Pharmacotherapy of adolescent attention deficit hyperactivity disorder: challenges, choices and caveats

A recent increase in stimulant treatment of adolescents with attention deficit hyperactivity disorder (ADHD) has been documented. Challenges in treating adolescent ADHD with methylphenidate or dextroamphetamine include compliance with frequent dosing, abuse potential and wear-off or rebound effects. Co-morbid anxiety, occurring in at least 30 percent of ADHD youths, is associated with lower rate of response to stimulants. The effective alternatives, tricyclic antidepressants or pemoline, are each associated with rare but serious toxicity. Bupropion has recently proven effective in controlled trials. Other noradrenergic or dopamine-enhancing agents such as venlafaxine and nicotine show some benefit in open trials. The need for more options in pharmacotherapy of ADHD is evidenced by rapid adoption in clinical practice of alternative and adjunctive medication despite lack of controlled research on efficacy and safety. The indications for long-term stimulant treatment of ADHD present some controversy, and highlight a need for more research on safety and efficacy through the lifespan. Thresholds for diagnosis are much lower with DSM than with ICD, and thresholds for treatment are contentious, given the performance-enhancing effects of stimulants in normal students. The endpoint for treatment is unclear, as stimulants are also effective in adult ADHD. Based on short- and intermediate-term studies to date, stimulant medication is clearly more efficacious than cognitive and behavioral strategies for the symptoms of ADHD. Longer term research is needed to determine whether sustained stimulant therapy will reduce the adverse emotional, behavioral and academic consequences of inattention and impulsivity in adolescents and adults.     

Cerebellar gray matter volume correlates with duration of cocaine use in cocaine-dependent subjects.

This study was conducted to explore differences in gray and white matter volume between cocaine-dependent and healthy comparison subjects using optimized voxel-based morphometry (VBM). Brain magnetic resonance imaging (MRI) and neuropsychological function tests were performed for 40 cocaine-dependent subjects (41.4+/-6.9 years, 27 men) and 41 healthy age- and sex-matched comparison subjects (38.7+/-8.8 years, 26 men). Optimally normalized whole brain MR images were segmented, modulated, smoothed, and compared between groups with statistical parametric mapping. The cocaine-dependent group had lower gray matter volumes in bilateral premotor cortex (Brodmann area (BA) 6, 8; 16.6%), right orbitofrontal cortex (BA 10, 15.1%), bilateral temporal cortex (BA 20, 38; 15.9%), left thalamus (12.6%), and bilateral cerebellum (13.4%) as well as lower right cerebellar white matter volume (10.0%) relative to the comparison group at a corrected p<0.05 for multiple comparisons. Duration of cocaine use negatively correlated with right and left cerebellar gray matter volumes (r=-0.37, r=-0.39, respectively). In cocaine-dependent subjects, lower cerebellar hemispheric gray and white matter volumes were correlated with deficits in executive function and decreased motor performance. This study reports that cocaine-dependent subjects have lower gray matter volumes in cerebellar hemispheres as well as in frontal, temporal cortex, and thalamus. These findings are the first to suggest that the cerebellum may be vulnerable to cocaine-associated brain volume changes, and that cerebellar deficits may contribute to neuropsychological deficits and motor dysfunction frequently observed in cocaine-dependent subjects.     

Adolescent Atomoxetine Treatment in a Rodent Model of ADHD: Effects on Cocaine Self-Administration and Dopamine Transporters in Frontostriatal Regions

Cocaine abuse and attention deficit/hyperactivity disorder (ADHD) are often comorbid. Preclinical research indicates that medial prefrontal (mPFC) and orbitofrontal (OFC) cortices are important neural substrates for both disorders. Using the spontaneously hypertensive rat (SHR) model of ADHD, we reported that adolescent treatment with the stimulant methylphenidate, a dopamine (DAT) and norepinephrine (NET) transporter inhibitor, enhanced cocaine self-administration during adulthood, and was associated with increased DAT function in mPFC. This study investigates the effects of atomoxetine ((R)-N-methyl-γ-(2-methylphenoxy)-benzenepropanamine hydrochloride) treatment, a selective NET inhibitor, during adolescence on cocaine self-administration and on DAT function and cell-surface expression in mPFC and OFC during adulthood. SHR acquired cocaine self-administration faster than Wistar–Kyoto and Wistar. Across cocaine doses, SHR earned more cocaine infusions and had higher progressive-ratio breakpoints than Wistar–Kyoto and Wistar, demonstrating that the SHR phenotype models comorbid ADHD and cocaine abuse. Prior atomoxetine treatment did not augment cocaine self-administration in SHR, but acquisition was enhanced in Wistar–Kyoto. No strain differences were found for DAT kinetic parameters or cellular localization in the vehicle controls. Atomoxetine did not alter DAT kinetic parameters or localization in SHR mPFC. Rather, atomoxetine decreased V_max and DAT cell surface expression in SHR OFC, indicating that inhibition of NET by atomoxetine treatment during adolescence indirectly reduced DAT function and trafficking to the cell surface in OFC, specifically in the ADHD model. Thus, atomoxetine, unlike methylphenidate, does not enhance vulnerability to cocaine abuse in SHR and may represent an important alternative for teens with ADHD when drug addiction is a concern.     

A Prospective Examination of the Association of Stimulant Medication History and Drug Use Outcomes among Community Samples of ADHD Youths

A continuing debate in the child psychopathology literature is the extent to which pharmacotherapy for children with attention-deficit/hyperactivity disorder (ADHD), in particular stimulant treatment, confers a risk of subsequent drug abuse. If stimulant treatment for ADHD contributes to drug abuse, then the risk versus therapeutic benefits of such treatment is greatly affected. We have prospectively followed an ADHD sample (N = 149; 81% males) for approximately 15 years, beginning at childhood (ages 8 to 10 years) and continuing until the sample has reached young adulthood (ages 22 to 24 years). The sample was originally recruited via an epidemiologically derived community procedure, and all youths were diagnosed with ADHD during childhood. We report on the association of childhood psychostimulant medication and subsequent substance use disorders and tobacco use. The substance use outcomes were based on data collected at three time points when the sample was in late adolescence and young adulthood (age range approximately 18 to 22 years old). We did not find evidence to support that childhood treatment with stimulant medication, including the course of stimulant medication, was associated with any change in risk for adolescent or young adulthood substance use disorders and tobacco use. These results from a community-based sample extend the growing body of literature based on clinically derived samples indicating that stimulant treatment does not create a significant risk for subsequent substance use disorders.     

ADHD,stimulant treatment in childhood and subsequent substance abuse in adulthood — A naturalistic long-term follow-up study

The purpose of the study was to estimate the risk of substance use disorder (SUD) and alcohol abuse in adulthood among children and adolescents with attention-deficit hyperactivity disorder (ADHD) compared to the background population. Furthermore, to examine whether the age at initiation and duration of stimulant treatment in childhood predicts SUD and alcohol abuse in adulthood. 208 youths with ADHD (183 boys; 25 girls) were followed prospectively. Diagnoses of SUD and alcohol abuse were obtained from The Danish Psychiatric Central Register. The relative risk (RR) of SUD and alcohol abuse for cases with ADHD, compared to the background population was 7.7 (4.3–13.9) and 5.2 (2.9–9.4), respectively. Female gender, conduct disorder in childhood and older age at initiation of stimulant treatment increased the risk of later SUD and alcohol abuse. Our results warrant increased focus on the possibly increased risk of substance abuse in females with ADHD compared to males with ADHD.     

A Prospective Examination of the Association of Stimulant Medication History and Drug Use Outcomes among Community Samples of ADHD Youths

A continuing debate in the child psychopathology literature is the extent to which pharmacotherapy for children with attention-deficit/hyperactivity disorder (ADHD), in particular stimulant treatment, confers a risk of subsequent drug abuse. If stimulant treatment for ADHD contributes to drug abuse, then the risk versus therapeutic benefits of such treatment is greatly affected. We have prospectively followed an ADHD sample (N = 149; 81% males) for approximately 15 years, beginning at childhood (ages 8 to 10 years) and continuing until the sample has reached young adulthood (ages 22 to 24 years). The sample was originally recruited via an epidemiologically derived community procedure, and all youths were diagnosed with ADHD during childhood. We report on the association of childhood psychostimulant medication and subsequent substance use disorders and tobacco use. The substance use outcomes were based on data collected at three time points when the sample was in late adolescence and young adulthood (age range approximately 18 to 22 years old). We did not find evidence to support that childhood treatment with stimulant medication, including the course of stimulant medication, was associated with any change in risk for adolescent or young adulthood substance use disorders and tobacco use. These results from a community-based sample extend the growing body of literature based on clinically derived samples indicating that stimulant treatment does not create a significant risk for subsequent substance use disorders.     

Shared and Unique Effects of Long-Term Administration of Methylphenidate and Atomoxetine on Degree Centrality in Medication-Naïve Children With Attention-Deficit/Hyperactive Disorder

BackgroundAlthough methylphenidate (MPH) and atomoxetine (ATX) can improve clinical symptoms and functional impairments in attention deficit/hyperactive disorder (ADHD), the underlying psychopharmacological mechanisms have not been clearly elucidated. Therefore, we aimed to explore the shared and unique neurologic basis of these 2 medications in alleviating the clinical symptoms and functional impairments observed in ADHD.MethodsSixty-seven ADHD and 44 age-matched children with typical development were included and underwent resting-state functional magnetic resonance imaging scans at baseline. Then patients were assigned to MPH, ATX, or untreated subgroups, based on the patients’ and their parents’ choice, for a 12-week follow-up and underwent a second functional magnetic resonance imaging scan. The treatment effect on degree centrality (DC) was identified and correlated with clinical symptoms and functional impairments in the ADHD group.ResultsBoth MPH and ATX normalized the DC value in extensive brain regions mainly involving fronto-cingulo-parieto-cerebellum circuits. However, ATX showed limited significant effects on the cerebellum compared with ADHD at baseline. The improvements in clinical symptoms were correlated with increased DC in the right inferior temporal gyrus in both MPH and ATX subgroups but showed opposite effects. The alleviation of functional impairments in the school/learning domain negatively correlated with decreased DC in the bilateral cerebellum after MPH treatment, and the family functional domain positively correlated with decreased DC in the cerebellum and negatively correlated with decreased DC in the postcentral gyrus after ATX treatment.ConclusionsBoth MPH and ATX can normalize abnormal brain functions that mainly involve the fronto-cingulo-parieto-cerebellum circuit in ADHD. Furthermore, the 2 medications showed shared and unique effects on brain functions to alleviate clinical symptoms and functional impairment.     

Association of gray matter volumes with general and specific dimensions of psychopathology in children

Childhood is an important time for the manifestation of psychopathology. Psychopathology is characterized by considerable comorbidity which is mirrored in the underlying neural correlates of psychopathology. Both common and dissociable variations in brain volume have been found across multiple mental disorders in adult and youth samples. However, the majority of these studies used samples with broad age ranges which may obscure developmental differences. The current study examines associations between regional gray matter volumes (GMV) and psychopathology in a large sample of children with a narrowly defined age range. We used data from 9607 children 9–10 years of age collected as part of the Adolescent Brain Cognitive Development^SM Study (ABCD Study^®). A bifactor model identified a general psychopathology factor that reflects common variance across disorders and specific factors representing internalizing symptoms, ADHD symptoms, and conduct problems. Brain volume was acquired using 3T MRI. After correction for multiple testing, structural equation modeling revealed nearly global inverse associations between regional GMVs and general psychopathology and conduct problems, with associations also found for ADHD symptoms (p_fdr-values ≤ 0.048). Age, sex, and race were included as covariates. Sensitivity analyses including total GMV or intracranial volume (ICV) as covariates support this global association, as a large majority of region-specific results became nonsignificant. Sensitivity analyses including income, parental education, and medication use as additional covariates demonstrate largely convergent results. These findings suggest that globally smaller GMVs are a nonspecific risk factor for general psychopathology, and possibly for conduct problems and ADHD as well.Subject terms: Human behaviour, Risk factors, Neuroscience     

Symptoms of Depression and ADHD in Relation to Stimulant Medication Misuse Among College Students

Background: The misuse of stimulant medications, commonly used for the treatment of attention-deficit/hyperactivity disorder (ADHD), is a concern on college campuses. Objective: This study sought to examine the relations between the misuse of stimulant medications and symptoms of depression and ADHD. Method: Eight hundred and ninety students ages 18–26 from one public university took a web-based survey including rating scales measuring symptoms of depression and ADHD. Results: The prevalence rate of misuse in the past year was 23%. Symptoms of depression were significantly related to misuse; however, once symptoms of ADHD were included in the analysis, depression was no longer a significant predictor. Further, there was not a significant interaction between ADHD and depression, but symptoms of ADHD were significantly related to misuse. Conclusions/Importance: Results suggest that attention difficulties may be one of the most important factors in predicting stimulant medication misuse. Therefore, prevention efforts to reduce the misuse of stimulant medication would be most successful when targeting students with symptoms of inattention.     

Selective Effects of Methylphenidate on Attention and Inhibition in 22q11.2 Deletion Syndrome: Results From a Clinical Trial

BackgroundAttention deficit and/or hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2 deletion syndrome (22q11DS) and frequently persists into adulthood. Although medication with stimulant has been demonstrated to be highly effective in idiopathic ADHD, evidence in 22q11DS is still scarce. Previous studies have shown safety and effectiveness of methylphenidate (MPH) on core symptoms of ADHD as well as improvement of associated cognitive deficits. However, only a limited number of cognitive domains have been explored.MethodsTwenty-three participants with 22q11DS and attention difficulties, aged 8–24 years, entered a clinical trial aiming to specify the effects of MPH on clinical symptoms, cognition, and daily-life behavior. The effects of treatment were compared with/without medication in a within-subject design. The trial included both participants naïve to the molecule and chronic users.ResultsBenefit from the treatment was demonstrated through a decrease in core ADHD symptoms, specifically inattention symptoms, and improvement of cognitive measures of attention and inhibition. Conversely, no significant change was found for other executive functions (such as cognitive flexibility, working memory, initiation), learning, or memory. Moreover, no significant improvement on ecological measures of daily-life executive functioning was found, possibly because of the short treatment period. We replicated safety, and although very frequent, side effects were of mild intensity and comparable with previous findings.ConclusionsThis study extends the current knowledge on the effects of MPH in patients with 22q11DS. Treatment was found to be effective for core ADHD symptoms and cognitive measures of attention and inhibition.     

Differences in regional blood volume during a 28-day period of abstinence in chronic cannabis smokers.

Cerebral blood volume (CBV) studies have provided important insight into the effects of illicit substances such as cannabis. The present study examined changes in regional blood volume in the frontal and temporal lobe, and the cerebellum during 28 days of supervised abstinence from cannabis. Dynamic susceptibility contrast MRI (DSCMRI) data were collected on 15 current, long-term cannabis users between 6 and 36 h after the subjects' last reported cannabis use (Day 0), and again after 7 and 28 days of abstinence. Resting state CBV images were also acquired on 17 healthy comparison subjects. The present findings demonstrate that at Day 7, cannabis users continued to display increased blood volumes in the right frontal region, the left and right temporal regions, and the cerebellum. However, after 28 days of abstinence, only the left temporal area and cerebellum showed significantly increased CBV values in cannabis users. These findings suggest that while CBV levels begin to normalize with continued abstinence from cannabis, specifically in frontal areas, other temporal and cerebellar brain regions show slower CBV decreases.     

Stimulant Medication for ADHD in Opioid Maintenance Treatment

Objective: The use of central stimulant medication in adults with attention deficit hyperactivity disorder (ADHD) who receive opioid maintenance treatment remains controversial and empirical evidence is limited. Because of the abuse potential of stimulant drugs, Norway has restrictions on prescribing central stimulants to individuals who have substance use disorders or who are on opioid maintenance treatment. In this naturalistic study, we describe experiences from a program through which central stimulant medication was administered to patients with ADHD receiving opioid maintenance treatment. Methods: This report is based on a program evaluation of a combined treatment project designed to provide stimulant medication to patients with adult ADHD who were receiving opioid maintenance treatment. As part of the clinical treatment, patients were monitored closely for any medical issues or adverse medication reactions and provided regular urine samples for analysis and information regarding demographics, treatment goals, legal involvement, diagnoses, substance abuse, and ADHD symptoms. Monitoring occurred at baseline, at 2 months (after patients being stabilized on the central stimulant), and again at 3, 6 and 24 months. Results: Among 42 patients initially offered the combined treatment, 24 were actually eligible, 20 started the combined treatment, and 10 stayed in the program. We were not able to identify a single major cause of treatment dropout. Patients reported significantly fewer symptoms of ADHD at the 6- to 8-week point, regardless of whether the data were analyzed using an intent-to-treat (all participants) or per-protocol (only those with complete data at all points) method. Even though self-assessed ADHD scores dropped significantly during treatment, the scores still remained fairly high, suggesting persistent functional impairment. Neither severe complications nor increase in substance abuse were observed during treatment with central stimulants. Conclusions: These findings show some promise with regard to the safety and utility of central stimulant medications for patients with ADHD who are receiving opioid maintenance treatment. Our study has methodological limitations, and systematic, well-designed clinical investigations are needed to increase the knowledge base.     

Hippocampal subfield morphology in monozygotic twins discordant for affective disorders

Unipolar and bipolar disorders aggregate in families and have been associated with a reduced gray-matter volume in hippocampal and prefrontal cortex. Here we used structural MRI to clarify whether abnormalities in hippocampal subfield and prefrontal cortical morphology are associated with familial vulnerability (i.e., changes present both in patients and unaffected relatives compared to healthy individuals), resilience (i.e., changes differentiating unaffected relatives and patients), or sequalae of illness in a sample of monozygotic twins. We investigated regional differences in gray-matter volume extracted using FreeSurfer 6.0 between remitted affected twins (AT) with either unipolar or bipolar disorder (n = 67), unaffected discordant co-twins (UT, n = 39), and low-risk twins (LT, n = 31) with no personal or first-degree family history of affective disorders. The UT showed greater bilateral hippocampal volumes compared to AT. Between group differences in left hippocampal volume were driven by greater cornu ammonis 1–3 and 4, subiculum and subfield of dentate gyrus. For the right hippocampus, differences were driven by greater hippocampal tail and subiculum. There was a trend for UT having a larger left hippocampus than LT, but no significant differences in hippocampal volumes between AT and LT. Outside the hippocampus, AT showed a smaller volume of left dorsomedial prefrontal cortex compared to LT. Our results suggest that larger volume of specific hippocampal subfields may be associated with resilience in healthy relatives of patients with an affective illness. Moreover, a smaller volume of left dorsomedial prefrontal cortex may reflect a sequalae of illness.Subject terms: Depression, Predictive markers, Depression     

Long-term use of stimulants in children with attention deficit hyperactivity disorder: safety, efficacy, and long-term outcome

The purpose of this review is to summarize existing data on the long-term safety and efficacy of stimulant treatment, and how long-term stimulant treatment of children with attention deficit hyperactivity disorder (ADHD) affects their outcome. Existing controlled studies of children with ADHD treated and untreated with stimulants, as well as long-term prospective follow-up studies, are reviewed. Children with ADHD treated with stimulants for as long as 2 years continue to benefit from the treatment, with improvements observed in ADHD symptoms, comorbid oppositional defiant disorder, and academic and social functioning, with no significant problems of tolerance or adverse effects. Long-term, prospective follow-up studies into adulthood show that stimulant treatment in childhood has slight benefits regarding social skills and self-esteem. Long-term adverse effects from stimulant treatment in childhood regarding adult height or future substance abuse have not been supported by existing studies.     

Modafinil treatment of amphetamine abuse in adult ADHD

Substance abuse is a frequent co-morbid condition of adult attention deficit hyperactivity disorder (ADHD). Treatment with conventional psychostimulants in adult ADHD with co-morbid stimulant abuse may be problematic. In this study, we report the case of a patient with adult ADHD with co-morbid amphetamine abuse who was treated successfully with the non-stimulant alertness-promoting drug modafinil. The drug resolved both the inattention/hyperactivity symptoms as well as the amphetamine abuse. Modafinil may be a suitable candidate treatment for adults with ADHD and stimulant abuse.     

Long-acting methylphenidate-OROS in youths with attention-deficit hyperactivity disorder suboptimally controlled with immediate-release methylphenidate: a study of cost effectiveness in The Netherlands

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is the most common mental health disorder in youths. Stimulants are the drugs of first choice in the treatment of ADHD. It has been suggested that full costs associated with the treatment of ADHD may be reduced by once-daily administration regimens of stimulants. OBJECTIVES: To estimate the cost effectiveness of treatment with long-acting methylphenidate osmotic release oral system (OROS) [Concerta] for youths with ADHD for whom treatment with immediate-release (IR) methylphenidate is suboptimal. STUDY DESIGN: We developed a Markov model to obtain an incremental cost-effectiveness ratio (ICER). The analysis covered 10 years, with a Markov cycle of 1 day. Costs (in 2005 euros ) included medication, consultations and treatment interventions, and additional costs for attending special education. Quality-adjusted life-years (QALYs) were used as the effectiveness measure. Outcome probabilities were taken from the medical literature and an expert panel of five child psychiatrists and paediatricians. Univariate sensitivity analyses were performed to assess the robustness of the base-case estimate. Multivariate sensitivity analysis was used to estimate a worst- and best-case ICER. RESULTS: The ICER of methylphenidate-OROS treatment in youths with ADHD for whom treatment with IR methylphenidate is suboptimal was euro 2004 per QALY. Total costs after 10 years were euro 15,739 for the IR methylphenidate pathway and euro 16,015 for the methylphenidate-OROS pathway. In the univariate sensitivity analysis, the ICER was sensitive to changes in resource use and the probability of stopping stimulant treatment in favour of IR methylphenidate. An ICER of 0 was reached with a 6.2% price reduction of methylphenidate-OROS. CONCLUSION: Methylphenidate-OROS is a cost-effective treatment for youths with ADHD for whom treatment with IR methylphenidate is suboptimal. Higher medication costs of methylphenidate-OROS were compensated for by savings on resource use, yielding similar 10-year costs compared with treatment with IR methylphenidate. Our analysis is sensitive to both clinical parameters and (differences in) resource utilization and costs between the groups modelled, warranting further research within clinical trials and observational databases, and into the full scope of costs.     

Use of double-blind placebo-controlled N-of-1 trials among stimulant-treated youths in The Netherlands: a descriptive study

OBJECTIVES: An N-of-1 trial is a double-blind placebo-controlled randomized trial to objectively and systematically evaluate the individual's response. This approach seems extraordinarily suitable for assessing the efficacy of stimulants in the treatment of attention deficit hyperactivity disorder (ADHD). The aim is to examine the use of N-of-1 trials among youths in the Netherlands, the protocols used, and the continuation of stimulant treatment thereafter. METHODS: Physicians requesting N-of-1 trials with stimulants were interviewed about their rationale and protocol. Prevalence and continuation were investigated by extracting N-of-1 trials among youths <20 years of age from a large pharmacy dispensing database for 2000-2004. RESULTS: The main purpose of N-of-1 trials mentioned by physicians was the assessing of individuals' response and dose-finding. Trial length, dosing schedule and efficacy assessment differed per physician. Trials consisted of a maximum of two treatment periods per dose. The annual percentage of youths starting stimulant treatment with an N-of-1 trial fluctuated between 0.6% (3/462) and 3.3% (10/301). No statistical significant difference could be detected between the continuation of stimulant treatment with or without an N-of-1 trial (p = 0.71). CONCLUSIONS: N-of-1 trials with stimulants are infrequently and not optimally used in the Netherlands. The results of N-of-1 protocols described by physicians are of questionable value, due to the small number of treatment periods per dose. More uniformity in the protocols would make it easier to encompass the N-of-1 methodology in physicians' daily practice.     

A positron emission tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predicting treatment response.

A hallmark symptom of attention-deficit hyperactivity disorder (ADHD) is an excess of motoric behavior or hyperactivity. Methylphenidate (MPH) is known to reduce hyperactivity in individuals with ADHD. Yet little is known about how it alters neural activity and how this relates to its clinical effects. The goal of this study is to examine MPH-induced changes during resting brain metabolism, and to examine how these changes correlate with measures of behavioral response to the drug. Measures of regional cerebral blood flow (rCBF) using positron emission tomography (PET) were acquired at rest for ten adult subjects with ADHD during both an unmedicated state and after a 3-week period of chronic dosing with a clinically optimal dose of MPH. Compared with the on-MPH condition, the off-MPH condition was associated with relative increases in rCBF bilaterally in the precentral gyri, left caudate nucleus, and right claustrum. The on-MPH condition was associated with relative increases in rCBF in the cerebellar vermis. A correlational analysis measured the relation between rCBF in the off-medication condition to change in ADHD ratings between the off- and on-MPH condition to identify brain regions associated with treatment response. The degree of change in the ratings was negatively correlated with rCBF increases in the midbrain, cerebellar vermis, and the precentral and middle frontal gyri in the off-MPH condition. The majority of these brain regions are involved in the planning and execution of motor behavior. These data suggest that MPH modulates brain regions associated with motor function to achieve a reduction in ADHD symptoms.