Proton pump inhibitor use among adults: Mapping the landscape of PPI use and exploring its effect on cancer risk and mortality

Background and aims: Proton pump inhibitors (PPIs) are commonly prescribed drugs that are used to treat acid-related disorders of the gastrointestinal tract. Over the last decade, PPI use has repeatedly been shown to be increasing worldwide, causing concerns due to reports of unsubstantiated long-term use and potential adverse effects. However, PPIs have also been suggested to promote antineoplastic effects in certain cancer settings via inhibition of specialized proton pumps. These proton pumps are involved in pH regulation in eukaryotic cells and believed to act as facilitators for the acidification of the tumor microenvironment (TME). Our aim was to use the population-based resources available to us in Iceland I) to assess the utilization of PPIs among the adult outpatient population residing in Iceland, II) to explore the potential of PPIs possessing an antineoplastic effect by estimating the risk among PPI users of being diagnosed with a first-time breast cancer, prostate cancer, or malignant melanoma, and III) to assess the potential influence of post-diagnosis PPI use on mortality among prostate cancer patients. Materials and methods: In study I, a drug utilization study, we investigated changes in overall PPI use between 2003 and 2015 among the adult outpatient population in Iceland. We estimated changes in annual incidence and prevalence, duration of PPI treatment, and the concurrent use of ulcerogenic drugs. In study II, a nested case-control study, we identified incident cases of breast cancer, prostate cancer, and malignant melanoma between 2005 and 2014. For each case, up to 10 controls were matched on birth-year, sex, and calendar year using risk-set sampling. Assessing ever use, high use, and cumulative use of PPIs, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. In study III, a cohort study, we identified patients diagnosed with prostate cancer between 2007 and 2012 among adult residents of Iceland aged between 40 and 85 years. PPI use was modelled in a time-dependent manner. Assessing post-diagnosis use, timing of use, cumulative use and stratifying by clinical stage we estimated the associations with prostate-cancer specific and all-cause mortality using Cox proportional hazard regression models and 95% CIs. Results: In study I, we observed a marked increase in outpatient PPI use over the last decade. Although the annual incidence remained fairly stable between 2003 and 2015, the annual prevalence estimates rose from 8.5 per 100 persons in 2003 to 15.5 per 100 persons in 2015. Furthermore, we found that prevalence increased with age and that 22% of patients were still being treated with PPIs one year after treatment initiation. In study II, we observed the following adjusted odds ratios (ORs) associated with ever use and high use of PPIs, respectively: 1.03 (95% CI: 0.92-1.16) and 0.97 (95% CI: 0.78-1.19) for breast cancer, 1.12 (95% CI: 1.00-1.25) and 1.20 (95% CI: 0.99-1.47) for prostate cancer, 0.84 (95% CI: 0.69-1.12) and 0.59 (95% CI: 0.40-1.13) for malignant melanoma. In secondary analyses, we did not observe a pattern consistent with a dose-response relationship for these three cancer types. In study III, we did not observe a statistically significant association between post-diagnosis PPI use and prostate cancer-specific mortality (HR 0.88; 95% CI: 0.52-1.48) or all-cause mortality (HR 1.02; 95% CI: 0.73-1.43). In secondary analyses, stratification by timing of use yielded adjusted HRs of 0.45 (95% CI: 0.21-0.98) among continuous PPI users and 1.12 (95% CI: 0.61-2.08) among new PPI users for prostate cancer-specific mortality. For all-cause mortality, we observed adjusted HRs of 0.67 (95% CI: 0.43-1.04) and 1.25 (95% CI: 0.82-1.92) among continuous users and new users, respectively. Stratification by cumulative dose and clinical stage did not reveal a statistically significant association with post-diagnosis PPI use for the mortality outcomes of interest. Conclusions: In conclusion, our observations indicate that PPI use in Iceland has increased considerably over the last decade; especially among older adults. Additionally, a high proportion of patients were treated for longer periods than clinical guidelines recommend. Furthermore, our findings do not support a chemopreventive role of PPIs in attenuating the risk of being diagnosed with a first-time breast cancer, prostate cancer, or malignant melanoma. Finally, our results do not indicate that post-diagnosis PPI use influences mortality among prostate cancer patients.Inngangur og markmið: Prótónupumpuhemlar (PPI) eru sýrubindandi lyf sem eru almennt notuð við meðferð á ýmsum magasýrusjúkdómum. Notkun PPI lyfja er útbreidd á heimsvísu og sú umtalsverða aukning sem hefur orðið á notkun þeirra hefur verið gagnrýnd í ljósi mögulegrar ofnotkunar og óvissu sem ríkir um mögulegar skaðlegar aukaverkanir. Sýrubindandi virkni PPI hefur verið talin hafa möguleg krabbameinshindrandi áhrif vegna hæfni þeirra til að hindra virkni sérhæfðra sýruseytandi ensíma. Talið er að slík ensím taki þátt í myndun á súru utanfrumuumhverfi krabbameinsfruma. Markmið okkar var nota lýðgrundaða gagnagrunna á Íslandi til að I) kortleggja notkun PPI lyfja meðal fullorðinna einstaklinga á Íslandi, II) meta áhættu PPI notenda á því að greinast með brjóstakrabbamein, blöðruhálskirtilskrabbamein, eða sortuæxli í húð, og III) meta möguleg verndandi áhrif PPI lyfjanotkunar á lifun sjúklinga með blöðruhálskirtils–krabbamein. Aðferðir: Rannsókn I var lyfjanotkunarrannsókn þar sem við lýstum notkun PPI lyfja á árunum milli 2003 og 2015. Við áætluðum árlegt nýgengi og algengi PPI notkunar, lengd PPI lyfjameðferðar og samhliða notkun lyfja sem geta haft í för með sér blæðingar í meltingarvegi. Rannsókn II var tilfella-viðmiðsrannsókn þar sem tilfellin voru einstaklingar sem greindust með brjóstakrabbamein, blöðruhálskirtilskrabbamein og sortuæxli á milli 2005 og 2014. Hvert og eitt krabbameinstilfelli pöruðum við saman við allt upp að 10 viðmið eftir almanaksári, fæðingarári, og kyni. Við áætluðum PPI notkun þátttakenda, þ.e. hvort leyst hefði verið út að minnsta kosti eina PPI lyfjaávísun, hvort notkun væri ≥1000 skilgreindum dagskömmtum (DDDs) og heildarnotkun og reiknuðum út gagnlíkindahlutföll (ORs) og 95% öryggisbil (CIs) fyrir áhættuna á því greinast. Rannsókn III var hóprannsókn þar sem einstaklingar á aldursbilinu 40 til 85 ára sem greindust með krabbamein í blöðruhálskirtli á milli 2007 og 2012 mynduðu rannsóknarhópinn. Við áætluðum upphaf PPI notkunar (fyrir eða eftir greiningu), heildarnotkun og lagskiptum eftir klínískri stigun. PPI notkun var meðhöndluð sem tímaháð breyta og Cox aðhvarfsgreining var notuð til að reikna út hættuhlutfall (HRs) fyrir dauða af völdum blöðruhálskirtilskrabbameins annars vegar og dauða af öllum orsökum hins vegar með 95% öryggismörkum (CI). Niðurstöður: Niðurstöður úr rannsókn I sýndu að heildarnotkun PPI lyfja á Íslandi fór ört vaxandi á rannsóknartímabilinu. Þótt nýgengi hafi haldist stöðugt jókst algengi PPI notkunar úr 8.5 á hverja 100 einstaklinga árið 2003 yfir í 15.5 á hverja 100 einstaklinga árið 2015. Ennfremur, reyndist algengi hækka með hækkandi aldri og 22% sjúklinga var enn að nota PPI einu ári eftir að meðferð hófst. Niðurstöður úr rannsókn II bentu ekki til þess að PPI notkun hafi í áhrif á krabbameinsáhættu (ORs 1.03; 95% CI: 0.92-1.16 fyrir brjóstakrabbamein, 1.12; 95% CI: 1.00-1.25 fyrir blöðruhálskirtilskrabbamein og 0.84; 95% CI: 0.69-1.12 fyrir sortuæxli). Sömuleiðis virtist PPI notkun ≥1000 DDDs ekki hafa áhrif (OR 0.97; 95% CI: 0.78-1.19 fyrir brjóstakrabbamein, 1.20; 95% CI: 0.99-1.47 fyrir blöðruhálskirtilskrabbamein, og 0.59; 95% CI: 0.40-1.13 fyrir sortuæxli). Niðurstöður okkar bentu ekki til þess að tengsl væru á milli heildarnotkunar á PPI og áhættunnar á því að greinast með brjóstakrabbamein, blöðruhálskirtilskrabbamein, eða sortuæxli. Niðurstöður úr rannsókn III bentu ekki til þess að PPI notkun eftir greiningu hefði áhrif á líkur á dauða af völdum blöðruhálskirtilskrabbameins (HR 0.88; 95% CI: 0.52-1.48) eða dauða af öllum orsökum (HR 1.02; 95% CI: 0.73-1.43). Upphaf PPI notkunar virtist ekki hafa áhrif, en HRs fyrir dauða af völdum blöðruhálskirtilskrabbameins voru 0.45 (95% CI: 0.21-0.98) meðal sjúklinga sem notuðu PPI lyf samfellt bæði fyrir og eftir greiningu og 1.12 (95% CI: 0.61-2.08) á meðal nýrra PPI notenda. HRs fyrir dauða af öllum orsökum voru 0.67 (95% CI: 0.43-1.04) á meðal sjúklinga sem notuðu PPI samfellt og 1.25 (95% CI: 0.82-1.92) á meðal nýrra PPI notanda. Lagskipting eftir heildarnotkun PPI lyfja og klínískri stigun leiddi ekki ljós tölfræðilega marktækt samband á milli PPI notkunar og lifunar. Ályktun: Niðurstöður verkefnisins benda til þess að PPI notkun hafi aukist umtalsvert á Íslandi yfir síðasta áratuginn; sér í lagi hjá eldri einstaklingum. Þar að auki er stór hluti sjúklinga meðhöndlaður lengur en mælt er með í klínískum leiðbeiningum fyrir lyfin. Niðurstöður okkar benda hvorki til þess að PPI notkun hafi áhrif á áhættu á brjóstakrabbameini, blöðruhálskirtils–krabbameini, eða sortuæxlum, né að hún hafi áhrif á lifun meðal sjúklinga með krabbamein í blöðruhálskirtli

Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder : a Nordic cohort study

Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND: Antipsychotics are increasingly used among women of childbearing age and during pregnancy. OBJECTIVE: To determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders. Design Population-based cohort study, including a sibling analysis. Setting Nationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016). Participants 4 324 086 children were eligible for inclusion to the study cohort. Intervention Antipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use. Main outcome measures Non-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors. FINDINGS: Among 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD. DISCUSSION: Our findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics. CLINICAL IMPLICATIONS: Results regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.Peer reviewe

Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder : a Nordic cohort study

Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND: Antipsychotics are increasingly used among women of childbearing age and during pregnancy. OBJECTIVE: To determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders. Design Population-based cohort study, including a sibling analysis. Setting Nationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016). Participants 4 324 086 children were eligible for inclusion to the study cohort. Intervention Antipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use. Main outcome measures Non-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors. FINDINGS: Among 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD. DISCUSSION: Our findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics. CLINICAL IMPLICATIONS: Results regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.Peer reviewe

Ræsing og ferill bráðra bólguviðbragða í kjölfar liðskiptaaðgerðar á mjöðm

Þegar líkaminn verður fyrir skaðlegu áreiti bregst hann við með því að framkalla bólgusvar. Við eðlilegt ástand þá hjaðnar bólgan að ákveðnum tíma liðnum en í einstaklingum sem glíma við króníska bólgusjúkdóma á borð við iktsýki og psoriasis viðhelst bólgan sem leiðir til þess sjúklega bólguástands sem einkennir þessa sjúkdóma. Það hefur reynst erfitt að kortleggja nákvæmlega ræsingu bólguferilsins í mönnum m.t.t. frumuboðefna og þeirra frumuhópa sem taka þátt í bólgusvarinu. Því hafa menn brugðið á það ráð að nota ýmis rannsóknarmódel til þess að rannsaka ræsingu ónæmiskerfisins í bólgusvari. Liðskiptaaðgerð á mjöðm er stöðluð valaðgerð sem framkallar kröftugt bólgusvar og hefur því verið notuð sem módel við rannsóknir á ræsingu ónæmiskerfisins í bráðu bólgusvari. Markmið verkefnisins var að rannsaka ræsingu ónæmiskerfisins í kjölfar liðskiptaaðgerðar á mjöðm m.t.t. valinna frumuhópa ónæmiskerfisins og viðloðunarsameinda á T-frumum. Það var gert með því að mæla tjáningu yfirborðssameinda á frumunum í frumuflæðisjá og heildarfjölda í sjálfvirku frumutalningartæki. 23 einstaklingar samþykktu þátttöku í rannsókninni. Tekin voru sýni á fjórum tímapunktum; fyrir aðgerð, 6 klst eftir aðgerð, 24 klst eftir aðgerð og 48 klst eftir aðgerð. Helstu breytingarnar sem sáust voru á fjölda dauffrumna (e. neutrophils) sem jukust marktækt í kjölfar aðgerðar og náðu hámarki 6 klst eftir aðgerð. Sveiflur í fjölda annarra frumuhópa og viðloðunarsameinda voru mun hógværari sem bendir til þess að dauffrumur taki mestan þátt í því bráða bólgusvari sem verður í kjölfar liðskiptaaðgerðar á mjöðm

A search for novel genes on chromosomes 2p, 6q and 14q in an Icelandic high-risk breast cancer family

Um það bil 5-10% greindra einstaklinga með brjóstakrabbamein tilheyra fjölskyldum með háa tíðni meinsins. Um helmingur fjölskyldnanna er án tengsla við stökkbreytingar í þekktum krabbameinsgenum á borð við BRCA1 og BRCA2 og kallast BRCAx-fjölskyldur. Í undanfara þessa verkefnis var sýnt fram á tengsl svæða á litningum 2p, 6q og 14q við brjóstakrabbamein í einni íslenskri BRCAx-fjölskyldu (70234). Í heildina eru 554 gen innan svæðanna þriggja en í þessu verkefni, skilgreint sem fyrsti hluti rannsóknarinnar, var ákveðið að raðgreina 274 gen. Markmið verkefnisins var að finna stökkbreytingar í einhverjum þessara gena sem teldust líklegar til þess að valda aukinni hættu á myndun brjóstakrabbameins. Roche 454 raðgreiningarniðurstöður fjögurra sýna úr meðlimum 70234 mynduðu grunn verkefnisins. Kímlínubreytileikar sem voru sameiginlegir með sýnunum fjórum voru teknir fyrir og lagt var mat á hvaða breytileikar væru líklegastir til þess að hafa áhrif á virkni þeirra gena sem báru þá. Fyrst var horft til breytinga af þremur gerðum; breytinga sem valda hliðrun á lesramma, þeirra sem kalla fram ótímabæran stöðvunartákna og splæsibreytinga. Því næst var horft til próteinkóðandi basabreytinga sem leiða til amínósýruskipta. SIFT og polyphen2 voru notuð til þess að leggja mat á mögulega skaðsemi slíkra breytinga. Að lokum voru breytingar á öðrum svæðum skoðaðar. Kandídatbreytingar voru skimaðar í óvöldum sjúklingahópi og viðmiðunarhópi og einnig í völdum fjölskylduefnivið. Kíkvaðratpróf var notað til þess að leggja mat á hvort tölfræðilega marktækur munur væri á samsætutíðni milli hópa. Heildarfjöldi sameiginlegra kímlínu breytileika var 1540. Þar af voru 146 breytileikar staðsettir á próteinkóðandi svæðum. Skimað var fyrir fjórum próteinkóðandi breytileikum og tveimur utan slíkra svæða, þar af einni splæsibreytingu. Ekki reyndist vera tölfræðilega marktækur munur á samsætutíðni þessara breytinga milli hópa. Engar stökkbreytingar fundust sem líklegar eru til þess að skýra aukna tilhneigingu til myndunar brjóstakrabbameins í fjölskyldu 70234. Næsta skref er að raðgreina þau 280 gen innan svæðanna þriggja sem ekki voru raðgreind í þessum fyrsta hluta rannsóknarinnar.It has been estimated that approximately 5-10% of breast cancer cases arise within high-risk hereditary breast cancer families. A little less than half of these familial cases have not shown linkage to pathogenic mutations within known cancer genes such as BRCA1 and BRCA2. Those families are generally referred to as BRCAx families. In a previous genome wide search for breast cancer linkage, performed at our laboratory, three highly suggestive signals were found at chromosomes 2p, 6q and 14q in one Icelandic BRCAx family (70234). There are a total of 554 genes to be found within the three regions combined. However, this project, defined as the first phase of a sequencing study on family 70234, revolved around the sequencing of 274 out of those 554 genes. The aim of the project was to identify pathogenic mutations in one or more of these genes in family 70234. Resequencing data, obtained via the Roche 454 sequencing platform, from four samples from family 70234 was the base of this project. Germline variants that were shared across all four samples were identified and evaluated for their possible pathogenicity. Firstly, all frameshift, nonsense and splice-site mutations among the shared variants were identified. Secondly, non-synonymous variants were identified and evaluated. SIFT and polyphen2 were used for the prediction of which non-synonymous SNPs were most likely to have a detrimental effect on the protein products of the genes harbouring them. Thirdly, shared variants within other regions of the genome were considered. Candidate variants were screened for in groups of controls and unselected breast cancer cases, as well as in a group of selected samples from other Icelandic hereditary breast cancer families. A chi-square test was used to evaluate whether there was a statistically significant difference in allele frequency between groups. The total number of shared germline variants identified was 1540. The number of variants within protein coding regions was 146. Four candidate protein coding variants were screened for and their allele frequency within the groups was estimated. Two non-coding variants were screened for as well, thereof one splice-site mutation. None of the candidate variants turned out to have a statistically significant difference in allele frequency when the groups were compared. We were not successful in identifying mutations that are likely to explain the increased breast cancer risk for members of family 70234. The next steps involve the sequencing of the 280 genes within the regions on chromosomes 2p, 6q and 14q that were not included in this phase of the study

Proton-pump inhibitors among adults: a nationwide drug-utilization study

Background: The use of proton-pump inhibitors (PPIs) has grown worldwide, and there are concerns about increased unsubstantiated long-term use. The aim of the study was to describe the real-world use of PPIs over the past decade in an entire national population. Methods: This was a nationwide population-based drug-utilization study. Patterns of outpatient PPI use among adults in Iceland between 2003 and 2015 were investigated, including annual incidence and prevalence, duration of use, and dose of tablet used (lower versus higher), as well as the proportion of PPI use attributable to gastroprotection. Results: We observed 1,372,790 prescription fills over the entire study period, of which 95% were for higher-dose PPIs. Annual incidence remained stable across time (3.3–4.1 per 100 persons per year), while the annual prevalence increased from 8.5 per 100 persons to 15.5 per 100 persons. Prevalence increased with patient age and was higher among women than men. Duration of treatment increased with patients’ age (36% of users over 80 years remained on treatment after 1 year compared with 13% of users aged 19–39 years), and was longer among those initiating on a higher dose compared with a lower dose. The proportion of PPI users concurrently using nonsteroidal anti-inflammatory drugs decreased over the study period, while the proportion concurrently using acetylsalicylic acid, oral anticoagulants, or platelet inhibitors increased. Conclusions: In this nationwide study, a considerable increase in overall outpatient use of PPIs over a 13-year period was observed, particularly among older adults. Patients were increasingly treated for longer durations than recommended by clinical guidelines and mainly with higher doses

Supplementary Material, supplementary_material – Proton-pump inhibitors among adults: a nationwide drug-utilization study

<p>Supplementary Material, supplementary_material for Proton-pump inhibitors among adults: a nationwide drug-utilization study by Óskar Ö. Hálfdánarson, Anton Pottegård, Einar S. Björnsson, Sigrún H. Lund, Margret H. Ogmundsdottir, Eiríkur Steingrímsson, Helga M. Ogmundsdottir and Helga Zoega in Therapeutic Advances in Gastroenterology</p

International trends in antipsychotic use:A study in 16 countries, 2005-2014

The objective of this study was to assess international trends in antipsychotic use, using a standardised methodology. A repeated cross-sectional design was applied to data extracts from the years 2005 to 2014 from 16 countries worldwide. During the study period, the overall prevalence of antipsychotic use increased in 10 of the 16 studied countries. In 2014, the overall prevalence of antipsychotic use was highest in Taiwan (78.2/1000 persons), and lowest in Colombia (3.2/1000). In children and adolescents (0-19 years), antipsychotic use ranged from 0.5/1000 (Lithuania) to 30.8/1000 (Taiwan). In adults (20-64 years), the range was 2.8/1000 (Colombia) to 78.9/1000 (publicly insured US population), and in older adults (65+ years), antipsychotic use ranged from 19.0/1000 (Colombia) to 149.0/1000 (Taiwan). Atypical antipsychotic use increased in all populations (range of atypical/typical ratio: 0.7 (Taiwan) to 6.1 (New Zealand, Australia)). Quetiapine, risperidone, and olanzapine were most frequently prescribed. Prevalence and patterns of antipsychotic use varied markedly between countries. In the majority of populations, antipsychotic utilisation and especially the use of atypical antipsychotics increased over time. The high rates of antipsychotic prescriptions in older adults and in youths in some countries merit further investigation and systematic pharmacoepidemiologic monitoring