Macey L. Murray

Attention-deficit hyperactivity disorder: treatment discontinuation in adolescents and young adults

BACKGROUND Symptoms of attention-deficit hyperactivity disorder (ADHD) are known to persist into adulthood in the majority of cases. AIMS To determine the prevalence of methylphenidate, dexamfetamine and atomoxetine prescribing and treatment discontinuation in adolescents and young adults. METHOD A descriptive cohort study using the UK General Practice Research Database included patients aged 15-21 years from 1999 to 2006 with a prescription for a study drug. RESULTS Prevalence of prescribing averaged across all ages increased 6.23-fold over the study period. Overall, prevalence decreased with age: in 2006, prevalence in males dropped 95% from 12.77 per 1000 in 15-year-olds to 0.64 per 1000 in 21-year-olds. A longitudinal analysis of a cohort of 44 patients aged 15 years in 1999 demonstrated that no patient received treatment after the age of 21 years. CONCLUSIONS The prevalence of prescribing by general practitioners to patients with ADHD drops significantly from age 15 to age 21 years. The fall in prescribing is greater than the reported age-related decrease in symptoms, raising the possibility that treatment is prematurely discontinued in some young adults in whom symptoms persist.

Epidemiologic features of antipsychotic prescribing to children and adolescents in primary care in the United Kingdom

OBJECTIVE. The goal was to investigate the epidemiologic features of antipsychotic prescribing to children and adolescents in general practice in the United Kingdom. METHODS. A total of 384 participating general practices from the United Kingdom General Practice Research Database were used to identify patients 0 to 18 years of age who were prescribed ≥1 antipsychotic medication between January 1, 1992, and December 31, 2005. Annual age-specific prevalences and incidences of antipsychotic prescribing were calculated. RESULTS. The overall prevalence of use of all antipsychotics increased from 1992 (0.39 users per 1000 patient-years) to 2005 (0.77 users per 1000 patient-years). The prescribing prevalence for patients 7 to 12 years of age almost tripled between 1992 (0.23 users per 1000 patient-years) and 2005 (0.61 users per 1000 patient-years). Atypical antipsychotic prescribing increased 60-fold from 1994 (0.01 users per 1000 patient-years) to 2005 (0.61 users per 1000 patient-years). However, typical antipsychotic prescribing decreased significantly from 2000 (0.44 users per 1000 patient-years) to 2005 (0.18 users per 1000 patient-years). The incidences for typical and atypical antipsychotics showed trends similar to those of the respective prevalences. However, the overall incidence (number of new starters) for all antipsychotics was relatively stable between 1992 and 2005, which suggests that patients remain on treatment longer. CONCLUSIONS. The overall prevalence of antipsychotics almost doubled between 1992 and 2005; however, the rate of increase was much lower than the reported figures in the United States. The prescribing of atypical antipsychotic drugs has increased despite the lack of conclusive evidence showing their superiority over older conventional antipsychotics. Additional investigation is required to evaluate their efficacy and safety in children and adolescents.

Cessation of attention deficit hyperactivity disorder drugs in the young (CADDY)--a pharmacoepidemiological and qualitative study.

OBJECTIVES To estimate the prevalence of attention deficit hyperactivity disorder (ADHD) pharmacological treatment, and its demographic and clinical details, and to estimate the proportion of patients in the target group who stopped ADHD treatment and investigate possible factors for continuation or cessation of treatment. DESIGN A pharmacoepidemiological study using an automated database and a qualititative study using patient interviews. Part 1 was a pharmacoepidemiological study that provided accurate data on use and cessation of ADHD drugs. Part 2 was an in-depth interview study to investigate the reasons, processes and outcomes of treatment cessation. SETTING Part 1: primary care using the General Practice Research Database (GPRD). Part 2: secondary and tertiary care paediatric clinics, child and adolescent mental health and adult mental health clinics in London, Nottingham, Dundee and Liverpool. PARTICIPANTS Part 1: patients were 15-21 years old during the study period (1 January 2001 and 31 December 2004), had at least one prescription for methylphenidate, dexamfetamine or atomoxetine and had at least 1 year of research-standard data available in the GPRD. Part 2: patients fulfilled Part 1 criteria, had a diagnosis of ADHD as detected by a predefined algorithm and had been treated with methylphenidate, dexamfetamine or atomoxetine for at least 1 year. Child and adolescent psychiatrists, adult psychiatrists and paediatricians involved in the treatment of young people with ADHD were also interviewed as part of the study. RESULTS Part 1: prevalence of prescribing averaged across all ages increased eightfold, from 0.26 per 1000 patients in 1999 to 2.07 per 1000 patients in 2006. The increase in prevalence in the younger patients was less evident in the older patients. Prevalence in 15-year-old males receiving a study drug prescription increased from 1.32 per 1000 patients in 1999 to 8.31 per 1000 patients in 2006, whereas the prevalence in 21-year-olds rose from 0 per 1000 patients in 1999 to 0.43 per 1000 patients in 2006. Survival analysis showed that the rate of treatment cessation largely exceeded the estimated rate of persistence of ADHD. The reduction in prescribing was most noticeable between 16 and 17 years of age. Kaplan-Meier analysis showed that approximately 18% of patients restarted treatment if they had stopped treatment after the age of 15. Patients who restarted treatment were more likely to restart within the first year following treatment cessation. Part 2: the Child Health and Illness Profile (CHIP) was chosen as the quality of life questionnaire for the Part 2 study because the CHIP-CE scale has been validated in children with ADHD in the UK. Because of the age range of participants, the adolescent version (CHIP-AE) was administered to patients after interview. Of the 15, a total of nine patients finished the questionnaire. Interviews showed that although some young people felt able to cope after stopping medication, others felt the need to restart to control symptoms. Some patients had difficulty re-engaging with services and clinicians recognised the lack of services for young adults. Patients continuing on treatment considered cessation as an option for the future, but were concerned about the process of stopping and its impact on behaviour. CONCLUSIONS Part 1 study demonstrated that the prevalence of prescribing by GPs to patients with ADHD dropped significantly from age 15 to 21. The fall in prescribing was greater than the reported age-related decrease in symptoms, raising the possibility that treatment is prematurely discontinued in some young adults where ADHD symptoms persist. Part 2 of the study identified that some young adults had difficulty in obtaining treatment after discharge from paediatric services. Future work should include randomised placebo-controlled trials into long-term treatment with stimulants, particularly methylphenidate.OBJECTIVE(S) To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications. DATA SOURCES Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies. REVIEW METHODS The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out. RESULTS In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results. CONCLUSION(S) All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

Drug use in children: Cohort study in three European countries

Objective To provide an overview of drug use in children in three European countries. Design Retrospective cohort study, 2000-5. Setting Primary care research databases in the Netherlands (IPCI), United Kingdom (IMS-DA), and Italy (Pedianet). Participants 675 868 children aged up to 14 (Italy) or 18 (UK and Netherlands). Main outcome measure Prevalence of use per year calculated by drug class (anatomical and therapeutic). Prevalence of “recurrent/chronic” use (three or more prescriptions a year) and “non-recurrent” or “acute” use (less than three prescriptions a year) within each therapeutic class. Descriptions of the top five most commonly used drugs evaluated for off label status within each anatomical class. Results Three levels of drug use could be distinguished in the study population: high (>10/100 children per year), moderate (1-10/100 children per year), and low (<1/100 children per year). For all age categories, anti-infective, dermatological, and respiratory drugs were in the high use group, whereas cardiovascular and antineoplastic drugs were always in the low use group. Emollients, topical steroids, and asthma drugs had the highest prevalence of recurrent use, but relative use of low prevalence drugs was more often recurrent than acute. In the top five highest prevalence drugs topical inhaled and systemic steroids, oral contraceptives, and topical or systemic antifungal drugs were most commonly used off label. Conclusion This overview of outpatient paediatric prescription patterns in a large European population could provide information to prioritise paediatric therapeutic research needs.

The epidemiology of pharmacologically treated attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults in UK primary care

BackgroundAttention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder characterised by the symptoms of inattention, impulsivity and hyperactivity. ADHD was once perceived as a condition of childhood only; however increasing evidence has highlighted the existence of ADHD in older adolescents and adults. Estimates for the prevalence of ADHD in adults range from 2.5–4%. Few data exist on the prescribing trends of the stimulants methylphenidate and dexamfetamine, and the non-stimulant atomoxetine in the UK. The aim of this study was to investigate the annual prevalence and incidence of pharmacologically treated ADHD in children, adolescents and adults in UK primary care.MethodsThe Health Improvement Network (THIN) database was used to identify all patients aged over 6 years with a diagnosis of ADHD/hyperkinetic disorder and a prescription for methylphenidate, dexamfetamine or atomoxetine from 2003–2008. Annual prevalence and incidence of pharmacologically treated ADHD were calculated by age category and sex.ResultsThe source population comprised 3,529,615 patients (48.9% male). A total of 118,929 prescriptions were recorded for the 4,530 patients in the pharmacologically treated ADHD cohort during the 6-year study. Prevalence (per 1000 persons in the mid-year THIN population) increased within each age category from 2003 to 2008 [6–12 years: from 4.8 (95% CI: 4.5–5.1) to 9.2 (95% CI: 8.8–9.6); 13–17 years: from 3.6 (95% CI: 3.3–3.9) to 7.4 (95% CI: 7.0–7.8); 18–24 years: from 0.3 (95% CI: 0.2–0.3) to 1.1 (95% CI: 1.0–1.3); 25–45 years: from 0.02 (95% CI: 0.01–0.03) to 0.08 (95% CI: 0.06–0.10); >45 years: from 0.01 (95% CI: 0.00–0.01) to 0.02 (95% CI: 0.01–0.03). Whilst male patients aged 6-12 years had the highest prevalence; the relative increase in prescribing was higher amongst female patients of the same age - the increase in prevalence in females aged 6–12 years was 2.1 fold compared to an increase of 1.9 fold for their male counterparts. Prevalence of treated ADHD decreased with increasing age. Incidence (per 1000 persons at risk in the mid-year THIN population) was highest for children aged 6–12 years.ConclusionsA trend of increasing prescribing prevalence of ADHD drug treatment was observed over the period 2003–2008. Prevalence of prescribing to adult patients increased; however the numbers treated are much lower than published estimates of the prevalence of ADHD. This study has added to the limited knowledge on ADHD prescribing in primary care, particularly in the area of drug treatment in adulthood.

A drug utilisation study of antidepressants in children and adolescents using the General Practice Research Database.

Aims: To characterise prescribing patterns of antidepressants (ATDs) to children and adolescents aged ⩽18 years in the UK. Methods: Subjects issued at least one ATD prescription between 1 January 1992 and 31 December 2001 were identified from the UK General Practice Research Database. Prescribing patterns, annual prevalence, morbidity patterns, and time to discontinuation of ATD use were identified. Results: A total of 24 976 subjects received 93 091 prescriptions; 51 868 (55.7%), 38 429 (41.3%), and 2708 (2.9%) prescriptions were for tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and other ATDs respectively. ATD prevalence increased 1.7-fold from 1992 to 2001. TCA prevalence decreased by 30% from 3.6 to 2.5 per 1,000; SSRI prevalence increased 10 times from 0.5 to 4.6 per 1,000. In new ATD users aged ⩽10 years, the most common diagnosis associated with TCA use was nocturnal enuresis (75.1%); in those aged ⩾15 years, it was depression (45.8%). Depression was also associated with SSRI use (69.0%). For new users with depression, the median treatment durations for TCAs and SSRIs were 30 and 58 days respectively. TCA users were more likely to terminate treatment than SSRI users (TCAs v fluoxetine: 1.40, 95% CI 1.32 to 1.47; non-fluoxetine SSRIs v fluoxetine: 1.01, 95% CI 0.96 to 1.07). Conclusions: SSRIs have gained popularity for the treatment of depression compared with TCAs. TCAs are still used despite their lack of efficacy in prepubertal depression and their moderate effect in adolescents. However, >50% of subjects discontinue treatment after two months, with TCA users stopping earlier than SSRI users.

Use of selective serotonin reuptake inhibitors in children and adolescents.

Depression is a serious condition, associated with considerable morbidity and mortality; selective serotonin reuptake inhibitors (SSRIs) were commonly used in its treatment in child and adolescent psychiatry until recently. In the wake of the recent UK Committee on Safety of Medicines (CSM) advice, we conducted a rapid review of current available information on SSRIs and suicidality (suicidal ideation, self-harm and suicide attempt) in children and adolescents from clinical trials and epidemiological studies. There is insufficient safety information from the randomised controlled trials to confirm a definite association between SSRIs and suicidality. Furthermore, analysis of suicide and antidepressant prescribing trends in three countries and a large case-control study do not support the hypothesis that there is a link between use of SSRIs and death caused by suicide. Regulatory agencies and the media should have strict guidelines for the management of information relating to the treatment of this condition so that clinicians can make properly informed decisions.We suggest clinical guidelines for managing depression in children and adolescents. SSRIs should not be considered for use as first-line treatment in mild or moderate depression of childhood, where psychological interventions such as cognitive behaviour therapy or interpersonal therapy are the mainstay. SSRIs should be considered when there is severe depression that does not respond to psychological interventions; when the child is suicidal and is admitted as an inpatient, is severely depressed or has bipolar depression despite adequate doses of mood-stabilisation agents; or when the child or family prefers pharmacotherapy to psychological interventions and gives informed consent. Local bodies of clinicians or peer groups should agree protocols and acceptable guidelines, taking into consideration the type of patients being assessed, the availability of nonpharmacological intervention, and the benefit-risk ratio of the pharmacological intervention. It is important that parents (and patients when possible) be given accurate information regarding the current controversy over SSRI prescribing. More research into the use of SSRIs in childhood depression is urgently required.

Effects of the committee on safety of medicines advice on antidepressant prescribing to children and adolescents in the UK

AbstractBackground: Psychotropic medication prescribing for children and adolescents rose significantly between 2000 and 2002, including antidepressant prescribing. In 2003, the Committee on Safety of Medicines (CSM) advised against using venlafaxine or any selective serotonin receptor inhibitor (SSRI), with the exception of fluoxetine, for childhood and adolescent depression. The aim of this study was to compare the prevalence and incidence of children and adolescents who were prescribed antidepressants in UK primary care, before and after the CSM advice on antidepressant prescribing. We also compared paediatric antidepressant prescribing trends from Mediplus data with national antidepressant prescribing trends in England from the Prescription Pricing Authority (PPA). Methods: The Disease Analyzer-Mediplus database contains anonymised primary care records for about 3 million patients. Eligible patients were aged ≤18 years and received ≥1 antidepressant prescription between 2000 and 2004. Antidepressants were grouped according to the CSM advice and the British National Formulary. Prevalence and incidence were calculated. The prevalences of 2000, 2002 and 2004 were compared using a Chi-squared test. PPA data on antidepressant prescribing rates were compared with paediatric antidepressant prescribing rates from Mediplus. Results: 5718 children and adolescents received a total of 25 542 prescriptions between 2000 and 2004. The median number of prescriptions per patient was two (interquartile range 1–5). Common indications included depression and anxiety. Antidepressant prevalence increased from 2000 to 2002 (from 5.4 to 6.6 patients per 1000 people), with a rise in the number of patients prescribed venlafaxine and SSRIs. However, between 2002 and 2004 there was a decrease in antidepressant prevalence (from 6.6 to 5.7 per 1000). The prevalence of CSM-contraindicated antidepressants (citalopram, escitalopram, fluvoxamine, paroxetine, sertraline and venlafaxine) declined by a third (from 3.1 to 2.0 per 1000), but there was no change in fluoxetine prevalence (from 2.1 to 2.3 per 1000). The number of patients prescribed tricyclic antidepressants dropped marginally (from 2.0 to 1.7 per 1000). Incidences followed the same trends as the prevalences, but there was a 48% reduction in the incidence of CSM-contraindicated antidepressants between 2002 and 2004. National antidepressant prescribing trends increased; paediatric prescribing trends were similar to national trends between 2000 and 2003; however, there was a 27% reduction in the paediatric prescribing rate of CSM-contraindicated antidepressants between 2002 and 2004. Conclusion: Since 2003, fewer children and adolescents have been prescribed antidepressants in primary care. However, fluoxetine and non-SSRI antidepressant prevalences have not risen, implying that they are not prescribed as alternative treatments. This study shows that the CSM advice has had a significant effect in reversing the rising prevalence of antidepressant prescribing to children and adolescents in primary care.

Changing trends in antiepileptic drug prescribing in girls of child-bearing potential

Objective: To characterize trends in prescribing carbamazepine (CBZ), sodium valproate (VPA) and lamotrigine (LTG) in adolescent females in the UK and to examine possible reasons for changing trends. Design: Population-based observational study. Setting: UK General Practice Research Database between 1 January 1993 and 31 December 2006. Patients: 12–18-year-old subjects who were issued ⩾1 CBZ, VPA or LTG prescription. Main outcome measures: Prescribing prevalences stratified by age, gender and antiepileptic drug. Results: 5417 patients (47.6% females) were prescribed 147 111 prescriptions for CBZ (34.5%), VPA (38.6%) or LTG (26.9%). The prevalence of LTG prescribing in females increased from 0.08 (95% CI 0.04 to 0.12) to 0.80 (95% CI 0.70 to 0.89) per 1000 female population. Conversely, the prevalence in females of CBZ and VPA prescribing significantly decreased from 1.00 (95% CI 0.85 to 1.15) to 0.51 (95% CI 0.44 to 0.58) and from 0.94 (95% CI 0.80 to 1.09) to 0.63 (95% CI 0.55 to 0.72), respectively. This 10-fold rise in LTG prescribing in females is much higher than the fivefold rise in males from 0.09 (95% CI 0.05 to 0.14) to 0.47 (95% CI 0.40 to 0.54) per 1000 male population. Conclusion: The practice of prescribing antiepileptic drugs in adolescents has changed gradually over the last decade. More females aged 12–18 years are prescribed LTG than CBZ or VPA and the increase is much greater than for males. The increase in LTG prescribing mirrors a corresponding decrease in both VPA and CBZ. Concerns about potential problems to offspring appear to be affecting prescription trends in adolescent females of child-bearing potential.

Comparison of antiepileptic drug prescribing in children in three European countries.

Purpose:  Antiepileptic drug (AED) use in young people is increasing. However, evidence of its use at a multinational level is limited. This study aims to characterize AED prescribing in the young in three European countries and to assess the capacity of drug safety surveillance.