Epidemiologija, farmakoepidemiologija ter primerjalna učinkovitost in sprejemljivost zdravil za zdravljenje hiperkinetične motnje otrok in mladostnikov : doktorska disertacija

Štuhec, Matej (author), Švab, Vesna (mentor), Locatelli, Igor (co-mentor)

Motnja pozornosti s hiperaktivnostjo (ADHD) je pogosto diagnosticirana nevropsihiatrična motnja pri otrocih in mladostnikih. Približno 30–50 % otrok diagnosticiranih v otroštvu ima simptome v odraslem obdobju. V večini evropskih držav je motnja opredeljena kot hiperkinetčna motnja (HKM) in v Severni Ameriki kot ADHD. Kljub določenim diagnostičnim razlikam v obeh klasifikacijah številni avtorji navajajo pri objavah skoraj izključno kratico ADHD, ki je uporabljena tudi v tej disertaciji. Ne glede na določene razlike v kriterijih med obema klasifikacijama, se za zdravljenje uporabljajo enaka zdravila. Prevalenca ADHD v svetu med otroci in mladostniki je 8–10 % in med odraslimi 2,5–4 %. Natančen vzrok ADHD ni znan, a ima breme motnje veliki vpliv na zdravstveni sistem in družbo. Število diagnosticiranih bolnikov z ADHD po svetu raste. V Sloveniji se obseg diagnostike in zdravljenja ADHD zaradi večje pozornosti in prepoznavanja povečuje. Kljub pomenu ADHD na javno zdravje, epidemiologija in poraba zdravil ADHD v Srednji in Vzhodni Evropi, vključujoč Slovenijo, nista dobro raziskani. Glede na ameriške in evropske smernice zdravljenje bolnikov z ADHD vključuje zdravljenje z zdravili in nefarmakološko zdravljenje. Atomoksetin (ATX) in metilfenidat (MPH) v različnih oblikah imata dovoljenje za promet z zdravilom v Sloveniji, Evropi in številnih drugih državah. ADHD se lahko zdravi tudi z bupropionom (BUP), tricikličnimi antidepresivi in nekaterimi drugimi zdravili. Zdravljenje ADHD lahko traja celo življenje. Zdravila za zdravljenje ADHD so do danes bila dobro raziskana; zaradi pomanjkanja kliničnih raziskav o učinkovitost BUP primanjkuje tudi raziskav o primerjalni učinkovitosti BUP z drugimi zdravili. Namen doktorskega dela je bilo oceniti parametre epidemiologije ADHD in porabe zdravil ADHD v Sloveniji, jih primerjati z drugimi državami ter oceniti primerjalno učinkovitost in sprejemljivosti zdravil za ADHD z uporabo metaanalize. Najprej je bil opravljen pregled različnih podatkovnih zbirk, kjer so bili iskani članki: s smernicami za zdravljenje ADHD z zdravili, s splošnimi podatki o epidemiologiji ADHD in primerjalni učinkovitosti in varnost zdravil za ADHD. V tem delu je najprej opisano zdravljenje ADHD z zdravili. Metilfenidat s kombinacijo takojšnjega in podaljšanega sproščanja (OROS-MPH), metilfenidat s takojšnjim sproščanjem (IR-MPH) in ATX imajo odobreno indikacijo za zdravljenje otrok in mladostnikov z ADHD v Sloveniji. MPH je zdravilo prve izbire glede na smernice. Upoštevanje farmakokinetičnih parametrov izbranega zdravila in morebitno medsebojno delovanje zdravil prispeva k zmanjšanju simptomov ADHD, lažji izbiri zdravila in določitvi ustreznega režima odmerjanja. Izid zdravljenja z zdravili je mogoče spremljati s standardiziranimi vprašalniki, ki so na voljo. Odrasle z ADHD je mogoče zdraviti z enakimi zdravili kot otroke in mladostnike, pogosto z maksimalnimi dovoljenimi odmerki, ki so učinkoviti in varni pri otrocih in mladostnikih. V Sloveniji ima samo ATX odobreno indikacijo za zdravljenje odraslih z ADHD. Pregledni članek o tem poglavju je bil objavljen v Zdravniškem vestniku.Nacionalnih podatkov incidence in prevalence ADHD diagnoz pri otrocih in mladostnikih v literaturi ni bilo na voljo. V ta namen so bili zgrajeni različni epidemiološki modeli za izračun incidence in prevalence ADHD pri otrocih in mladostnikih v Sloveniji in rezultati primerjani z rezultati zahodnih držav. Za potrebe modela so bili analizirani podatki iz podatkovne baze Nacionalnega inštituta za varovanje zdravja Republike Slovenije v obdobju 1997–2012. V letu 1997 je bila letna incidenca ADHD diagnoz 0,0317 % , v letu 2000 je narasla na 0,0469 % in na 0,0823 % v letu 2012. Prevalenca ADHD diagnoz je bila ocenjena v letu 2012 med 722 in 767 na 100.000 otrok in mladostnikov. Ob dosedanjem trendu naraščanja števila bolnikov z ADHD bo prevalenca ADHD diagnoz v letu 2020 6,3-krat večja kot v letu 1997 in 1,3-krat večja kot v letu 2012. Regionalne razlike v epidemiologiji ADHD v Sloveniji obstajajo, vendar jih je zaradi nizkih incidenčnih vrednosti, vedno boljših prometnih povezav, velikosti države in neenakomernega dostopa do specialistov težko primerjati med seboj. ADHD je pogosta duševna motnja v Sloveniji, vendar je v primerjavi z zahodnimi državami redkeje diagnosticirana. Uporabljeni epidemiološki modeli so lahko široko uporabni. Z vsemi epidemiološkimi modeli so bili izračunani primerljivi rezultati. Rezultati kažejo na potrebo po pravočasnih intervencijah v Sloveniji na tem področju, ne samo v psihiatričnih službah za otroke in mladostnike, ampak tudi v primarnem zdravstvu in psihiatričnih službah za odrasle, kjer bi bilo potrebno ADHD bolje prepoznavati. Članek iz te raziskave je bil poslan v revijo Croatian Medical Journal. Drugi del raziskovanja je obsegal raziskovanje na področju porabe zdravil za ADHD. Glavni namen je bil predstavitev trenda nacionalne porabe zdravil za zdravljenje ADHD v Sloveniji. Nacionalni podatki ambulantne porabe zdravil in njihovih stroškov za obdobje 2001–2012 so bili pridobljeni iz podatkovne baze Zavoda za zdravstveno zavarovanje Slovenije. Iz podatkovne baze so bili uporabljeni podatki porabe zdravil in vrednosti celokupnih stroškov za zdravila v evrih. OROS-MPH, IR-MPH in ATX so imeli dovoljenje za promet z zdravilom v Sloveniji in so vključeni v raziskavo. Amfetamini v Sloveniji niso bili na voljo, zato so bili izključeni iz raziskave. Poraba zdravil za ADHD je v Sloveniji narasla iz 0,0537 definiranih dnevnih odmerkov (DDD)/1000 prebivalcev/dan v 2001 na 0,0687 DDD/1000 prebivalcev/dan v letu 2006 in na 0,3076 DDD/1000 prebivalcev/dan v letu 2012. Povečana poraba je predvsem posledica povečane porabe OROS-MPH in ATX, medtem ko se je poraba IR-MPH zmanjšala. V raziskovanem obdobju so celotni stroški zdravil narasli za 31-krat. Od leta 2007 do 2010 so celotni stroški za zdravila narasli za 14-krat in v obdobju 2010–2012 za 11,4 %. Poraba zdravil za ADHD je v slovenskih regijah različna in rast porabe neenakomerna. Največja poraba vseh zdravil za ADHD v letu 2012 je bila na področju Kopra in Novega mesta in najmanjša na področju Murske Sobote in Nove Gorice. V Sloveniji so tudi regionalne razlike v predpisovanju ATX, odstopanja so predvsem na področju Krškega in Novega mesta. Neustrezno predpisovanje je mogoče povezati z neupoštevanjem evropskih smernic in vpliva farmacevtskega marketinga v korist predpisovanja ATX v teh regijah. Po uvedbi novih zdravil za ADHD v Sloveniji je njihovo predpisovanje hitro naraščalo. Spremembe v vzorcu predpisovanja zdravil so v Sloveniji evidentne, predvsem glede povečane porabe OROS-MPH in ATX ter hitrega zmanjšanja porabe IR-MPH. Članek iz te raziskave je bil sprejet v objavo v Journal of Child and Adolescent Psychopharmacology. Tretji del raziskovanja je obsegal področje učinkovitosti in sprejemljivosti zdravil za ADHD. Zdravila, ki se uporabljajo za zdravljenje ADHD, so bila glede tega že dobro raziskana, vendar je pomanjkanje primerjalnih raziskav med posameznimi zdravili glede učinkovitosti in sprejemljivosti, kjer bi primerjali BUP, lisdeksamfetamin (LDX), MPH in ATX. Z uporabo metaanalize je bila opravljena primerjava učinkovitosti in sprejemljivosti navedenih zdravil za zdravljenje simptomov ADHD. Opravljen je bil pregled literature dvojno slepih s placebom kontroliranih raziskav; vključene so bile samo vzporedne raziskave (izključene navzkrižne) pri otrocih in mladostnikih z ADHD, objavljene po letu 1950. V Pubmed/Medline in Clinicaltrials.gov je bila za iskanje virov uporabljena naslednja iskalna strategija: ‘motnja pozornosti s hiperaktivnostjo’ ALI ‘ADHD’ IN ‘ime učinkovine’. Kot primarni podatki so bile iz raziskav izluščene vse prekinitve v raziskavah zaradi vseh razlogov in uspeh pri zdravljenju. Razmerje obetov (OR) je bilo uporabljeno za sprejemljivost in standardizirana razlika povprečij (SMD) za učinkovitost. Prekinitve zdravljenja niso bile značilno manjše v primerjavi s placebom za ATX (OR = 0,91, 95 % CI, 0,66, 1,24) in LDX (OR = 0,60, 95 % CI, 0,22, 1,65), so bile značilno manjše za MPH (OR = 0,35, 95 % CI, 0,24, 0,52) ter niso bile značilno večje za BUP (OR = 1,64, 95 % CI, 0,50, 5,43). Velikosti učinka napram placebu so bile izražene kot SMD in znašajo: za BUP je -0,32 (95 % CI, -0,69, 0,05), le-ta se je izkazal za slabo učinkovitega, za ATX -0,68 (95 % CI, -0,76, -0,59), in za MPH -0,75 (95 % CI, -0,98, -0,52), ta dva sta se izkazala kot srednje učinkoviti terapiji v zmanjšanju simptomov, ADHD in LDX kot zelo učinkovit, SMD je -1,28 (95 % CI, -1,84, -0,71). BUP 0,32 (95 % CI, -0,69, 0,05) se je izkazal za slabo učinkovitega, ATX 0,68 (95 % CI, 0,59, 0,76), in MPH 0.75 (95 % CI, 0,52, 0,98) sta se izkazala kot srednje učinkoviti terapiji v zmanjšanju simptomov ADHD in LDX kot zelo učinkovit 1,28 (95 % CI, 0,71, 1,84). Iz rezultatov je razvidno, da ima LDX najboljše razmerje med koristmi in tveganji za zdravljenje ADHD pri otrocih in mladostnikih. Priporočilo uporabe LDX v tej populaciji je veliko. Ta metaanaliza je tretja metaanaliza, kjer so raziskovalci primerjali učinkovitost BUP, ATX in MPH in druga v primeru primerjave z LDX. Hkrati je ta metaanaliza prva nesponzorirana metaanaliza v literaturi, kjer so avtorji primerjali in analizirali prekinitve zdravljenja ATX, BUP, LDX in MPH. Članek iz te raziskave je bil poslan v revijo Journal of Affective Disorder. V zadnjem delu raziskovanja je opisana raziskava primera 17–letne slovenske bolnice z ADHD, ki je bila zdravljena z ATX (v preteklosti s klozapinom, levomepromazinom in ostalimi zdravili), ter diagnostike in zdravljenje, ki so privedli do podaljšanega bolnišničnega zdravljenja. ATX je bil uveden po sedmih letih zdravljenja. Po uvedbi ATX (60 mg dnevno) je prišlo do hitrega izboljšanja stanja. Po dveh mesecih zdravljenja z ATX so se pojavile palpitacije in izgube zavesti s povišanim srčnim utripom (115 utripov/minuto), sinusna aritmija in podaljšan QT interval (QTc = 540 ms). Zdravljenje z ATX je bilo takoj prekinjeno, čemur je sledilo izboljšanje kardiovaskularnega stanja. ATX je potrebno vključiti med zdravila, ki lahko povzročijo kardiovaskularne neželene učinke. Bolnica je bila zdravljena na psihiatričnem odelku za odrasle, kar kaže na pomanjkanje služb za ADHD v Sloveniji. Članek iz te raziskave je bil objavljen kot raziskava primera v obliki pisma uredniku v reviji Irish Medical Journal in predstavljen na četrtem Svetovnem kongresu ADHD, junija 2013 v Milanu v Italiji. Rezultati raziskave so prispevek k znanosti, ker predstavljajo nove podatke o epidemiologiji in porabi ADHD zdravil ter primerjalni učinkovitosti in sprejemljivosti zdravil za ADHD. Potrebno je nadaljnje raziskovanje na tem področju v Sloveniji in v drugih evropskih državah.

• Language: Slovenian
• Keywords: hiperkinetične motnje otrok, hiperkinetične motnje mladostnikov, farmakoepidemiologija, zdravljenje motenj, epidemiološki modeli, incidenca motenj, predpisovanje zdravil, disertacije
• Work type: Doctoral dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [M. Štuhec]
• Year: 2015
• Number of pages: 174 f.
• PID: 20.500.12556/RUL-143724
• UDC: 615.214:616.89-008.47-053.6(043.3)
• COBISS.SI-ID: 3811697
• Publication date in RUL: 11.01.2023

Secondary language

• Language: English
• Title: Epidemiology, pharmacoepidemiology, comparative efficacy and acceptability of drugs in treatment of attention deficit hyperactivity disorder in children and adolescents

Abstract

Attention deficit hyperactivity disorder (ADHD) is a commonly diagnosed neuropsychiatric disorder in childhood and adolescence. Worldwide about 30–50% of children diagnosed in childhood with ADHD continue to have symptoms into adulthood. In contrast to North America, ADHD is identified as hyperkinetic disorder (HKM) in most European countries and is therefore used also in this dissertation. Regardless of the differences in diagnostic criteria, the same medicines are used to treat ADHD and HKM. ADHD worldwide prevalence in the children and adolescents is 8–10% and in adults 2.5–4%. The exact cause of ADHD is not known, however its burden has a high impact on the healthcare system and the community. The number of people diagnosed with ADHD is increasing worldwide. In recent years, ADHD has been diagnosed and treated more frequently in Slovenia, primarily due to better recognition and more attention to the disorder. Despite its relevance in terms of public health, the epidemiology and ADHD medicine consumption of this disorder are not well established in many Central and Eastern European countries, including Slovenia. According to the European and American guidelines, the management of ADHD consists of nonpharmacological options, and pharmacotherapy, including stimulants and nonstimulants. Atomoxetine (ATX) and methylphenidate (MPH) in different forms have been approved for treatment of children and adolescents with ADHD in Slovenia, throughout Europe, and in many other countries. In addition, ADHD is also treated with bupropion (BUP), tricyclic antidepressants and some other drugs. ADHD treatment can be a lifelong one. Medications used to treat ADHD are well researched, but there is a lack of head-to-head comparative effectiveness trials between BUP and other drugs. The aim of this work was to estimate the Slovenian parameters of ADHD epidemiology and ADHD medicine consumption in comparison with the results of other countries, and to estimate the comparative effectiveness and acceptability of AHDH drugs using a meta-analysis. The first part of this research was a review of different databases to identify articles, which have investigated the pharmacotherapy guidelines for AHDH patients with general data of the ADHD epidemiology and comparative efficacy and safety of AHDH medicines. In this part, the pharmacotherapy for AHDH patients was highlighted. ATX, immediate-release MPH, and extended release MPH are approved to be used in children and adolescents with ADHD in Slovenia. According to the pharmacotherapy guidelines the drug of choice is MPH. Consideration of the pharmacokinetic parameters of the selected medicines and potential drug-drug interactions, if the patient is taking other medications, helps to reduce ADHD symptoms and to select the appropriate medicine and medicine dosing regimen. Clinical outcomes could be measured by standardized questionnaires, which are widely available. Adults are treated with the same medicines as children and adolescents, often with maximum approved doses, which also demonstrated to be safe and effective in treating children and adolescents. ATX is the only approved drug in Slovenia for the treatment of adult ADHD patients. The review article based on this review was published in the Slovenian Medical Journal (Zdravniški vestnik). The Slovenian incidence and prevalence of ADHD diagnosis in children and adolescents have not yet been reported in the literature, therefore several epidemiological models to calculate them were built. Since the epidemiological data on the prevalence of ADHD in Slovenia do not exist, our results were compared Slovenia with Western countries. The data from the National Institute of Public Health of the Republic of Slovenia for the years 1997–2012 were analyzed. In 1997, the annual incidence rate of ADHD diagnosis in Slovenia was 0.0317% and increased to 0.0469% in 2000 and to 0.0823% in 2012. The prevalence rate of ADHD diagnosis was estimated between 722 and 767 per 100,000 children and adolescents. If the increase persists, the prevalence of ADHD diagnosis in Slovenia in 2020 will be 6.3-fold higher than in 1997 and 1.3-fold higher than in 2012. There were some regional differences in the epidemiology of ADHD in Slovenia, but interregional comparison is not viable because of the low incidence of ADHD, better traffic connections, the small country size, and different levels of access to specialists. These epidemiological models could be widely applicable, especially in this part of Europe, where a registry of AHDH patients is not available. Almost identical results were calculated with all models. From these results, it can be concluded that ADHD in Slovenia is common, but it is still underdiagnosed in comparison with Western countries. Results also indicated a need for improved timely interventions in Slovenia, not only in child and adolescent psychiatry but also in primary settings and adult psychiatry, where ADHD should be recognized efficiently. The article based on this research was submitted in to the Croatian Medical Journal. The second part of research was in the field of drug consumption. The main aim was to present the pattern and the evolution of national ADHD drug consumption in Slovenia. For this purpose, the national consumption outpatient data for the period 2001–2012 and medication costs were obtained from the database of the Health Insurance Institute of Slovenia. Total medicine consumption per 1000 inhabitants per day and the total medication cost in euros were extracted. Only immediate-release methylphenidate (IR-MPH), methylphenidate-osmotic release oral delivery system (OROS-MPH) and atomoxetine (ATX) have been approved for ADHD in Slovenia and are included in this study. The amphetamines had not been available in Slovenia and were excluded from this study. ADHD medicine consumption increased in Slovenia from 0.0537 defined daily dose (DDD)/1000 inhabitants/day in 2001, to 0.0687 DDD/1000 inhabitants/day in 2006 and 0.3076 DDD/1000 inhabitants/day in 2012. The rise was largely due to an increase in OROS-MPH and ATX consumption, while the consumption of IR-MPH decreased rapidly. In the study period, the total cost of the medicines increased 31-fold. The total cost of ADHD medicines increased 14-fold during 2007–2010, and by only 11.4% during 2010–2012. The prescribed amounts of medicines for ADHD are the highest in the regions of Koper and Novo mesto and the lowest in the regions of Murska Sobota and Nova Gorica. There were regional differences in the ATX prescribing trend, for example, in Novo mesto and Krško. Inappropriate prescribing can be associated with noncompliance with European treatment guidelines and the impact of pharmaceutical marketing in favor of prescribing ATX in these regions. The changes in the pattern of prescribing medicine are evident in Slovenia, primarily in the increase of OROS-MPH and ATX consumption and in the rapid decrease of IR-MPH consumption. The article based on this research was accepted for publication in Journal of Child and Adolescent Psychopharmacology. The third part of this research was a comparison of ADHD medicines by their efficacy and acceptability. Individual ADHD medications have been well researched until now, but there is a lack of comparative effectiveness research among medications in terms of efficacy and acceptability, where BUP is compared with ATX, lisdexamfetamine (LDX)and MPH. Consequently, a meta-analysis, comparing the efficacy and acceptability of MPH, LDX, BUP and ATX for treating ADHD symptoms in children and adolescents was performed. A literature search was conducted to identify double-blind, placebo-controlled, noncrossover studies of ADHD in youth published after 1950. PubMed/Medline and Clinicaltrials.gov were searched using the key words "attention deficit hyperactivity disorder" or "ADHD" and "drug". All-cause treatment discontinuation and treatment score were the primary endpoints. Drug acceptability was calculated based on the odds ratio (OR), while efficacy was calculated based on the standardized mean difference (SMD). The absolute effect sizes versus placebo expressed in SMD were: BUP -0.32 (95% CI, -0.69, 0.05) showed small efficacy, ATX -0.68 (95% CI, -0.76, -0.59) and MPH -0.75 (95% CI, -0.98, -0.52) showed modest efficacy in reducing ADHD symptoms and LDX showed high efficacy -1.28 (95% CL, -1.84, -0.71). Treatment discontinuations were lower than with a placebo, nonsignificant for ATX (OR = 0.91; 95% CI, 0.66, 1.24) and LDX (OR = 0.60; 95% CI, 0.22, 1.65) and significantly higher (OR = 0.35; 95% CI, 0.24, 0.52) and nonsignificantly higher for BUP (OR = 1.64; 95% CI, 0.5, 5.43). The results suggest that LDX has the best benefit-risk balance and has promising potential for treating children and adolescents with ADHD. This meta-analysis is the third to compare BUP with LDX by their efficiacy and the second to further compare BUP with LDX. It is also the first nonsponsored meta-analysis that analyzes and reports on discontinuations of ATX, BUP, LDX and MPH. The article based on this research was submitted in to the Journal of Affective Disorders. In the last part, a case report of a 17-year old Slovenian ADHD adolescent treated with ATX, who was previously treated with clozapine and levomepromazine and other medicines was reported. The case was described to identify diagnostic and treatment gaps resulting in prolonged hospitalization. ATX was introduced after 7 years of treatment with several medicines. The introduction of ATX (60 mg daily) resulted in a gradual improvement of ADHD symptoms. After 2 months of treatment with ATX, palpitations and loss of consciousness were reported, along with an increased heart rate (115 bpm), sinus arrhythmia and a prolonged QT (QTc = 540 ms) interval. The therapy with ATX was abruptly discontinued and the patient recovered. ATX should be included among the causes of drug-induced cardiovascular adverse effects. The patient was treated in a psychiatric hospital for adults, which suggests a lack of services for the treatment of ADHD in Slovenia. The article in the Letter to the editor form based on this case study was published in the Irish Medical Journal and presented on the 4th World Congress on ADHD, From Childhood to Adult Disease 06–09 June 2013, Milan, Italy. These findings in the field of ADHD contribute new data on the epidemiology, ADHD medicine consumption and comparative efficacy and acceptability of ADHD drugs. Further investigation of ADHD in Slovenia and in Europe is suggested.