A question based approach to drug development

As shown in the previous case study, changing the development plan from phase/time oriented to question based can improve the insights on the information that needs to be obtained and will help display the priorities within the program. In conventional phase-based drug development, timing is not the most important issue, as long as studies are performed rapidly. In this thesis, it is shown that the order in which studies are performed has a significant impact on the efficiency and quality of the drug development process. The impact of this novel approach can best be demonstrated by calculation of the financial consequences of resolving the right questions at the right time, during the development of new compounds. This calculation is based on the real-option theory, applied to drug development questions. Simple decision analyses suffice to determine the best sequence of research projects, and detailed pharmaco-economic models are unnecessary for this purpose. The thesis also provides some examples of research projects that were performed at different stages of drug development, with widely different consequences for the values of the projects concernedUBL - phd migration 201

Assessment of neuroleptic-induced movement disorders in a naturalistic schizophrenia population

The prevalence and assessment of neuroleptic-induced movement disorders (NIMDs) in a naturalistic schizophrenia population that uses conventional neuroleptics were studied. We recruited 99 chronic schizophrenic institutionalized adult patients from a state nursing home in central Estonia. The total prevalence of NIMDs according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) was 61.6%, and 22.2% had more than one NIMD. We explored the reliability and validity of different instruments for measuring these disorders. First, we compared DSM-IV with the established observer rating scales of Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS) (for neuroleptic-induced parkinsonism, NIP) and Abnormal Involuntary Movement Scale (AIMS) (for tardive dyskinesia), all three of which have been used for diagnosing NIMD. We found a good overlap of cases for neuroleptic-induced akathisia (NIA) and tardive dyskinesia (TD) but somewhat poorer overlap for NIP, for which we suggest raising the commonly used threshold value of 0.3 to 0.65. Second, we compared the established observer rating scales with an objective motor measurement, namely controlled rest lower limb activity measured by actometry. Actometry supported the validity of BARS and SAS, but it could not be used alone in this naturalistic population with several co-existing NIMDs. It could not differentiate the disorders from each other. Quantitative actometry may be useful in measuring changes in NIA and NIP severity, in situations where the diagnosis has been made using another method. Third, after the relative failure of quantitative actometry to show diagnostic power in a naturalistic population, we explored descriptive ways of analysing actometric data, and demonstrated diagnostic power pooled NIA and pseudoakathisia (PsA) in our population. A subjective question concerning movement problems was able to discriminate NIA patients from all other subjects. Answers to this question were not selective for other NIMDs. Chronic schizophrenia populations are common worldwide, NIMD affected two-thirds of our study population. Prevention, diagnosis and treatment of NIMDs warrant more attention, especially in countries where typical antipsychotics are frequently used. Our study supported the validity and reliability of DSM-IV diagnostic criteria for NIMD in comparison with established rating scales and actometry. SAS can be used with minor modifications for screening purposes. Controlled rest lower limb actometry was not diagnostically specific in our naturalistic population with several co-morbid NIMDs, but it may be sensitive in measuring changes in NIMDs.Väitoskirjatyö "Assessment of neuroleptic-induced movement disorders in a naturalistic schizophrenia population" osoittaa, että kroonista skitsofreniaa sairastavilla, vanhoja psykoosilääkkeitä saavilla potilailla on runsaasti liikehäirioitä ja usein useampi liikehäiriö samanaikasesti. Tutkimus vertaili ja arvioi eri mittauskeinojen käyttökelpoisuutta vanhojen psykoosilääkkeiden aiheuttamien neurologisten haittavaikutusten arvioinnissa. Psykoosien lääkehoidon ensimmäistä kehitysvaihetta edustavat, 1950-luvulla käyttöön tulleet tavanomaiset psykoosilääkkeet ovat tehokkaita psykoosin ns. positiivisen oireisiin, mutta niiden käyttöä ovat rajoittaneet erilaiset haittavaikutukset. Keskeisimpiä näistä ovat mm. pakkoliikkeinä, vapinana ja jäykkyytenä ilmenevät neurologiset oireet, jotka esiintyessään heikentävät potilaan hoitomyöntyvyyttä, mikä vaarantaa pitkällä aikavälillä hoidon toteutumisen. Tästä johtuen kahden viimeisen vuosikymmenen aikana on pyritty kehittämään tehokkaampia ja paremmin siedettyjä psykoosilääkkeitä, joiden käyttömahdollisuudet kuitenkin vaihtelevat maasta toisen niiden korkeasta hinnasta johtuen. Tutkimus toteutettiin poikkileikkaustutkimuksena Viron suurimmassa psykiatrisessa hoitokodissa. Tutkimuksen osallistuneet 99 potilasta olivat keski-ikäisiä, pitkään skitsofrenian takia hoidettavina olleita potilaita, joista noin 80 prosenttia käytti vanhoja/ tavanomaisia psykoosilääkkeitä. Heistä noin 60 prosentilla oli todettavissa jokin neurologinen haittaoire, jonka esiintyvyyttä ja haittaavuutta arviointiin eri arviointimenetelmin sekä uutta tekniikkaa edustavalla aktometrialla. Tutkimuksessa käytettiin haastatteluun ja havainnointiin perustuvina mittausmenetelminä nykyiseen diagnostiseen järjestelmään perustuvaa liikehäiriöiden arvioitia, Barnesin akatisia-astekkoa (BARS), Simpson-Angusin parkinsonismiastekkoa (SAS) ja tardiivin dyskinesian arvioimiseksi epänormaalien tahattomien liikkeiden asteikkoa (AIMS). Aktometria osoittautui arviointiastekkojen rinnalla hyödylliseksi lisäarviointimenetelmäksi, joka ei kuitenkaan yksinään osoittautunut riittäväksi em. liikehäiriöiden alamuotojen erotusdiagnostiikassa

The comparative neuropsychology of dementia

PhD ThesisOn the basis of neuropathological, neurochemical, genetic, and clinical profile studies on patients, distinct forms of dementia, such as dementia with Lewy bodies (DLB), have been distinguished which were originally thought to be Alzheimer's disease (AD). Dementia with Lewy bodies is probably the second most common form of dementia in the elderly. In this thesis, a well characterised and investigated cohort of DLB and AD patients were compared to non-demented elderly controls in order to establish profiles of cognitive decline in these groups. Initially, comprehensively matched experimental groups were compared using the Cambridge Neuropsychological Test Automated Battery (CANTAB). The DLB group was less impaired than the AD group on a test of visual pattern recognition memory. However, the DLB group performed worse on a number of cognitive tests. Comparison of larger, carefully matched, experimental groups using the Cognitive Drug Research Computerised Assessment Battery (CDR) also revealed differences in the profile of cognitive impairment in DLB and AD. The DLB group showed more marked deficits in attentional abilities than the AD group. In particular, the DLB group were unable to sustain attention. Conversely, the DLB group were less impaired on a test of visual secondary recognition memory than the AD group. Further division of the DLB group into cases with and without persistent visual hallucinations revealed distinct patterns of cognitive impairment in these two groups. Generally, DLB cases with persistent visual hallucinations showed greater attentional and spatial working memory deficits than the DLB cases without persistent visual hallucinations. A final study compared decline in cognitive function over 1 year in DLB, AD and control groups. Similar rates of cognitive decline were identified in a number of cognitive domains in AD and DLB groups. In addition, disproportionate decline in the ability to sustain attention was identified in the DLB group. A comparative model relating known neuropsychological, neurochemical, and neuropathological features of DLB and AD was proposed

Opportunities for improving animal welfare in rodent models of epilepsy and seizures

Animal models of epilepsy and seizures, mostly involving mice and rats, are used to understand the pathophysiology of the different forms of epilepsy and their comorbidities, to identify biomarkers, and to discover new antiepileptic drugs and treatments for comorbidities. Such models represent an important area for application of the 3Rs (replacement, reduction and refinement of animal use). This report provides background information and recommendations aimed at minimising pain, suffering and distress in rodent models of epilepsy and seizures in order to improve animal welfare and optimise the quality of studies in this area. The report includes practical guidance on principles of choosing a model, induction procedures, in vivo recordings, perioperative care, welfare assessment, humane endpoints, social housing, environmental enrichment, reporting of studies and data sharing. In addition, some model-specific welfare considerations are discussed, and data gaps and areas for further research are identified. The guidance is based upon a systematic review of the scientific literature, survey of the international epilepsy research community, consultation with veterinarians and animal care and welfare officers, and the expert opinion and practical experience of the members of a Working Group convened by the United Kingdom's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs)

Esmase psühhoosiepisoodiga patsientide kognitiivne funktsionaalsus

Väitekirja elektrooniline versioon ei sisalda publikatsioonePsühhootiliste häirete puhul on tegemist bioloogiliste põhjustega aju toimimise eripäradega. Enamlevinud krooniline psühhootiline häire on skisofreenia, mille puhul võivad ilmneda psühhopatoloogilised ilmingud tajumises, mõtlemises, tunde- ja tahteelus. Üha suuremat kliinilist ja teadusuuringute põhist tähelepanu pööratakse häire avaldumise esmasele episoodile ning haiguse tuumsümptomina käsitletakse kognitiivse funktsionaalsuse omapära. Uurimustöö eesmärgiks oli iseloomustada esmase psühhootilise episoodi ilmnemise järgselt patsientide kognitiivsete funktsioonide sooritussuutlikkuse eripärasid võrreldes tervete eakaaslastega. Lisaks, hinnata patsientide objektiivselt mõõdetud ja subjektiivselt hinnatud kognitiivset funktsionaalsust ajalises dünaamikas ning kirjeldada aju morfoloogiliste tunnuste (ajukoore paksuse ja pindala) seoseid aju funktsionaalse toimimisega. Uuritavate kognitiivseid funktsioone hinnati arvutipõhise neuropsühholoogilise testipatarei abil, mille patsiendid läbisid võimalusel kuuekuulise ajaintervalliga ka teistkordselt. Hinnatud kognitiivsete funktsioonide valdkonnad olid: visuaalne ja ruumiline äratundmismälu, õppimisvõime, tähelepanu ümberlülitumisvõime, tegevuse planeerimis- ja täidesaatmisvõimekus, töömälu maht, töömälus oleva infoga toimetamisvõimekus, strateegiate kasutus ning infotöötluskiirus. Lisaks andsid patsiendid tagasisidet subjektiivselt tajutud kognitiivsete funktsioonide sooritussuutlikkuse kohta. Magnetresonantstomograafilise ajukuvamisuuringu kasutamine võimaldas määratleda osalejate ajukoore paksust ja pindala iseloomustavaid väärtuseid. Tulemustest selgus, et esmase psühhoosiepisoodi järgselt ilmneb patsientide grupi tasandil laiaulatuslik kognitiivsete funktsioonide sooritussuutlikkuse langus võrreldes tervete eakaaslastega. Patsientidel avalduv kognitiivne düsfunktsionaalsus ei piirdu üksnes kvantitatiivsete muutustega, neil esinevad lisaks ka kvalitatiivsed ehk funktsionaalsuse struktuurilised erinevused. Lisaks selgitasime, et hinnatud kognitiivsete funktsioonide sooritussuutlikkuse muutused ajas võivad ilmneda määra, viisi ja suuna erinevustes. Ilmnes, et objektiivselt mõõdetud ja subjektiivselt hinnatud vaimse tegevuse sooritussuutlikkus on teineteisest eristuvad ja tõenäoliselt teineteist täiendavad konstruktid. Saamaks laiapõhjalisemat ülevaadet patsiendi igapäevasest vaimsest toimimisest tuleks kasutada samaaegselt mõlemat lähenemist. Osalejate ajukuvamisuuringute ja neuropsühholoogiliste testide tulemuste seosteanalüüsidele tuginedes näitasime, et eeskätt morfoloogilised muutused eesaju, oimu- ja kiirusagara ning vöökääru aladel korreleeruvad kognitiivse funktsionaalsuse eripäradega. Lisaks ilmnesid erinevused aju struktuuri ja funktsiooni korrelatsioonimustrites haigete ja kontrollgruppi kuulujate osas. Uurimustöö tulemused rõhutavad kognitiivse düsfunktsionaalsuse kui haigusspetsiifilise tunnuse olemasolu juba kroonilise psühhootilise häire varajases staadiumis.Schizophrenia is a severe psychiatric disorder that has a strong biological basis and is characterized by disturbances in perception, thought, emotion, and behaviour. In the field of psychiatric research, there is growing interest in the early stage of the chronic psychotic disorder and mounting evidence suggests that compromised cognitive function is a core feature of the illness. Aims of the research were to characterize cognitive functioning of the first-episode psychosis/schizophrenia patients, and to study its relationships with subjectively perceived cognitive functioning and brain morphological parameters. A comprehensive computer-based neuropsychological battery was used. The battery included tests designed to assess subjects’ pattern and spatial recognition memory capacity, learning and rapid visual information processing abilities, shifting and flexibility of attention, spatial planning and executive functioning, and to evaluate participants’ ability to retain spatial information and manipulate these remembered items in their working memory, and to use strategies. Objective and subjective mental functioning data were collected at baseline and follow-up measures were completed approximately six months later, in the patients’ group. We used magnet resonance imaging technique to evaluate brain morphological (i.e., cortical thickness and cortical area) parameters. The results indicated that patients exhibited widespread cognitive impairments, and that the structure of underlying cognitive abilities as measured by a selection of neuropsychological tests is not the same for healthy individuals and patients with first-episode psychosis. The findings suggested that there is variability in the type, direction, and size of the changes of different cognitive functions over time among patients with first psychotic episode. Objectively measured and sujectively perceived cognitive functioning are two distinct and probably complementary constructs, and should be measured separately in order to attain a more comprehensive assessment of each patient’s day-to-day functioning. Furthermore, we demonstrated that morphological changes in frontal, temporal, parietal, and cingulate cortices may be related to the altered cognitive functioning among patients and that the brain structure-function relationships may be dissimilar for patients with first psychotic episode and healthy subjects. Our findings support continued efforts to elucidate cognitive dysfunction as a characteristic feature of the early stage of chronic psychotic disorder