Class of 2005 Abstract / Objectives: To describe the dosing of atypical antipsychotics among outpatients diagnosed with schizophrenia at a community mental health center in Tucson, AZ, and to contrast this to dosing recommendations set by the manufacturer during clinical trials. Methods: A prescription database from January 01, 2004 to July 31, 2004 was used to evaluate the dosing of atypical antipsychotics (Abilify®, Clozaril®, Geodon®, Seroquel®, and Zyprexa®) in patients with schizophrenia. The average daily doses were evaluated for differences from recommended dosing using the physician desk reference. Differences in dosing were also analyzed for gender and monotherapy vs. patients taking multiple atypical antipsychotics. Results: Overall differences in dosing when comparing gender and monotherapy vs. patients on multiple atypicals were not significant for all five atypical antipsychotics studied. Overall, Geodon® had the highest percentage (51.9%) of patients above recommended guidelines while Clozaril® and Seroquel® had the highest percentage (70.6% and 47.4% respectively) below recommended guidelines. Implications: This study illustrates that dosing of these atypical antipsychotics at this outpatient community mental health center differs for many patients with schizophrenia from the guidelines set by the companies during clinical trials. This information will aid in the prescribing of physicians at this community mental health center and will possibly lead to larger studies to further look at reasons for these differences in dosing.

Reports have linked atypical antipsychotics (AAPs) with weight gain. The polymorphic CYP2D6 involved in metabolism has been associated with medication morbidity. Eleven subjects receiving olanzapine were genotyped for CYP2D6 to examine the relationship between 2D6 and AAP weight gain. Using a linear regression, the dependent variable was percent change in body mass index (BMI). Genotype, dose and duration of treatment were independent. Genotype was significant (P < 0.0097) for those with a *1/*3 or *4 genotype experiencing a larger percent BMI change than those with a *1/*1 genotype. This may be due to increased olanzapine concentrations leading to increased exposure, which may trigger AAP weight gain.

Os antipsicóticos são drogas utilizadas no tratamento de muitos transtornos psiquiátricos, sendo classificados em dois grupos: típicos e atípicos. Os típicos formam o grupo de drogas que bloqueiam especialmente os receptores de dopamina e, por isto, causam efeitos colaterais característicos, que se manifestam através de sintomas extrapiramidais e podem terminar em discinesia tardia. Os atípicos apresentam eficácia antipsicótica similar à dos antipsicóticos típicos, mas produzem menos efeitos colaterais extrapiramidais e não causam discinesia tardia. Os antipsicóticos se ligam às proteínas plasmáticas, principalmente a albumina, a qual representa cerca de 60% do total das proteínas no soro humano. Neste trabalho estudamos os processos de interação de duas drogas antipsicóticas atípicas, risperidona e sulpirida, com as albuminas séricas humana (HSA) e bovina (BSA), através da técnica de supressão da fluorescência intrínseca do triptofano. A partir dos espectros de fluorescência, a análise dos dados foi feita obtendo-se os gráficos e as constantes de Stern-Volmer. A análise da supressão da fluorescência foi feita a partir da média aritmética dos dados oriundos dos experimentos realizados em cada condição adotada. Como a molécula da sulpirida é fluorescente desenvolvemos uma modelagem matemática do processo de interação, que nos permitiu então obter os dados referentes à supressão da fluorescência da proteína. Os resultados mostraram que a risperidona e a sulpirida suprimem a fluorescência de ambas albuminas por um processo de quenching estático, formando complexos droga-albumina. A risperidona tem uma afinidade com a HSA cerca de 6,5 vezes maior do que a sulpirida, a 37 oC. As constantes de associação calculadas para a interação risperidona-HSA, através da Teoria de Stern-Volmer, foram 1,43 ( 0,05) x 105 M-1, a 37 C, e 2,56 ( 0,09) x 105 M-1, a 25 C1; e para a sulpirida, 2,20 ( 0,08) x 104 M-1, a 37 C, e 5,46 ( 0,20) x 104 M-1, a 25 C. Como a taxa de quenching da BSA foi maior do que a da HSA, sugerimos que o sítio primário para a risperidona nas albuminas esteja localizado mais próximo ao domínio do triptofano 134 da BSA do que do domínio do triptofano 212 da HSA. O mesmo sugerimos com relação ao sítio para a sulpirida a 37 C. / Antipsychotics are drugs used to treat many psychiatric disorders. They are classified into two groups: typical and atypical. The typical group act blocking dopamine receptors in particular and it causes characteristic side effects with extrapyramidal symptoms, and can lead to tardive dyskinesia. The atypical group presents similar efficacy to typical group, but they produce less extrapyramidal side effects and does not cause tardive dyskinesia. Antipsychotics bind to plasmatic proteins, mainly to albumin, which represents about 60% of total human serum proteins. In this study we studied the interactions of two atypical antipsychotic drugs, risperidone and sulpiride, with human serum albumin (HSA) and bovine (BSA) through the technique of intrinsic tryptophan fluorescence quenching. From the fluorescence spectra, a data analysis was made to obtain Stern-Volmer plots and constants. Quenching analysis was performed used from using arithmetic means of data from experiments for each adopted condition. As sulpiride molecule is fluorescent, a mathematical modeling for interaction process was made. It allows us then to obtain the data referents to fluorescence quenching of protein. Results showed that risperidone and sulpiride quench the fluorescence for both albumins by static quenching process, forming complexes drug-albumin. The risperidone affinity to HSA is about 6.5 higher than supiride, at 37 oC. Stern-Volmer constants for interaction risperidone-HSA were 1.43 ( 0.05) x 105 M-1, at 37oC, and 2.56 ( 0.09) x 105 M-1, at 25 oC; and for sulpiride were 2.20 ( 0.08) x 104 M-1, at 37 oC, and 5.46 ( 0.20) x 104 M-1, at 25 oC. As the quenching ratio for BSA was higher than HAS, we suggested that the primary site for risperidone on albumin is closer of the domain of trypthophan 134 of BSA than the domain of trypthophan 212 of HAS. The same is suggested for the primary site of supiride at 37oC.

Dementia, a clinical condition that affects the psychological ability of patients, is distinguished by a significant overall decline in cognitive function that results in distorted perception. Guiding nursing practice in the long-term care (LTC) setting to decrease the unnecessary use of psychotropics is critical because doing so relates to the patients' quality of life and safety. In the LTC facility that served as the practicum site for this study, there was an observed overuse of psychotropic medications in the care of patients with dementia. The practice-focused question guiding this project asked whether a nursing staff development program would decrease the use of psychotropics in dementia patients. The purpose of the project was to inform nursing staff through an educational program on alternative methods to use when dementia patients exhibit increased disturbing behaviors. The conceptual framework for the project was the knowledge-to-action model. The nursing staff development program had a positive effect on the nursing staff as evidenced by a statistically significant improvement in knowledge and attitudes about the use of psychotropics in caring for dementia patients. The use of psychotropic in the dementia patient decreased from 22.32% to 15.77%, the lowest score achieved by the organization in 5 years. The dementia patients benefited from this project and its positive social change implications for nursing practice by decreasing dementia patients use of psychotropics, minimizing their side effects to the patients and providing an overall feeling of well-being.

The behavioral effects of drugs that act on the brain’s dopamine (DA) system change with repeated exposure to the drug. Antipsychotic drugs, that block DA receptors, produce progressively greater effects on behavior with repeated testing. For example, rats repeatedly treated with a low dose of the D2 receptor-preferring antagonist haloperidol do not initially exhibit catalepsy, a response quantified by time spent on a horizontal bar without active movement. However, with repeated drug-environment pairings animals show a reduction in exploration and increases in catalepsy. The current thesis examined the drug-environment relationship in catalepsy sensitization, and how different DA receptor subtypes control this phenomenon. Treatment with a D2, but not D3 or D1-like receptor-preferring antagonist produced catalepsy sensitization. Catalepsy sensitization developed in one test environment did not transfer to another environment. Similarly, rats with a history of haloperidol treatments outside of the test environment (unpaired group) did not exhibit significant catalepsy when given haloperidol for the first time prior to catalepsy testing. Previous exposure to the catalepsy test environment led to a more rapid development of catalepsy sensitization. Thus, drug-environment interaction is critical for the development and expression of catalepsy sensitization. Rats previously given haloperidol and tested with saline in the drug paired environment exhibited conditioned catalepsy. The acquisition of conditioned catalepsy is dependent on D1-like receptors, while its expression is dependent on D3 receptors. Conditioned catalepsy showed gradual day-to-day extinction with repeated saline treatment in the previously haloperidol-paired environment. Following extinction, the response to haloperidol in previously sensitized rats shifted from environment-specific to environment-independent suggesting that a putative haloperidol drug cue alone can elicit conditioned catalepsy. In summary, treatment with a D2, but not D1-like or D3 receptor-preferring antagonist in a particular test environment produces catalepsy sensitization, while acquisition of conditioned catalepsy is dependent on D1-like receptors, and its expression is dependent on D3 receptors. Importantly, the acquisition and expression of sensitization to haloperidol is conditional on the presence of drug-associated environmental stimuli. Our findings provide further insight into the current understanding of learning processes involved in the action of antipsychotic drugs and the dissociable effects of D1-like, D2 and D3 receptors controlling this phenomenon. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2012-08-12 15:51:00.467

Falls among older adults (age 65 years and older) residing in personal care homes (PCHs) are an important health concern. Atypical antipsychotic drugs (AADs) have been shown to be associated with fall risk among older adults. However, previous studies face some methodological limitations that affect the quality, consistency, and comparability of these studies. Therefore, a population-based study was undertaken to examine the effect of AAD use on the risk of falling among older PCH residents. A nested case-control study was conducted using the administrative healthcare records and Minimum Data Set for PCHs (MDS) housed at the Manitoba Centre for Health Policy in the Faculty of Medicine, University of Manitoba. The study period was from April 1, 2005 to March 31, 2007. Cases (n=626) were fallers as recorded in MDS. Using incidence density sampling, each case was matched to four controls on length of PCH stay, age, and sex (n=2,388). Exposure to AADs was obtained from the Drug Program Information Network database. Conditional logistic regression was used to model the effects of AAD use on the risk of falling while accounting for matching and for confounding of other covariates. While the adjusted odds of falling was statistically greater for AAD users versus nonusers (adjusted odds ratio = 1.60, 95% CI 1.10-2.32), this association was type and dose dependent. Compared to nonusers, the odds of falling was greater for quetiapine users, regardless of this drug's dose, and high dose risperidone users. On the other hand, low dose risperidone and olanzapine, irrespective of drug dose, use was not associated with the risk of falling. Furthermore, the effect of AAD use, in general, on the risk of falling was significantly greater for people with wandering problems (adjusted odds ratio = 1.84, 95% CI 1.09-3.09). Despite some methodological limitations, this research has provided some unique findings that enhance our understanding of AAD use as a fall risk factor. Study findings allow policymakers to further develop evidence-based interventions specific to AADs in order to better manage falls in the PCH setting. However, a great deal of research is still needed to address other important unanswered questions.

Falls among older adults (age 65 years and older) residing in personal care homes (PCHs) are an important health concern. Atypical antipsychotic drugs (AADs) have been shown to be associated with fall risk among older adults. However, previous studies face some methodological limitations that affect the quality, consistency, and comparability of these studies. Therefore, a population-based study was undertaken to examine the effect of AAD use on the risk of falling among older PCH residents. A nested case-control study was conducted using the administrative healthcare records and Minimum Data Set for PCHs (MDS) housed at the Manitoba Centre for Health Policy in the Faculty of Medicine, University of Manitoba. The study period was from April 1, 2005 to March 31, 2007. Cases (n=626) were fallers as recorded in MDS. Using incidence density sampling, each case was matched to four controls on length of PCH stay, age, and sex (n=2,388). Exposure to AADs was obtained from the Drug Program Information Network database. Conditional logistic regression was used to model the effects of AAD use on the risk of falling while accounting for matching and for confounding of other covariates. While the adjusted odds of falling was statistically greater for AAD users versus nonusers (adjusted odds ratio = 1.60, 95% CI 1.10-2.32), this association was type and dose dependent. Compared to nonusers, the odds of falling was greater for quetiapine users, regardless of this drug's dose, and high dose risperidone users. On the other hand, low dose risperidone and olanzapine, irrespective of drug dose, use was not associated with the risk of falling. Furthermore, the effect of AAD use, in general, on the risk of falling was significantly greater for people with wandering problems (adjusted odds ratio = 1.84, 95% CI 1.09-3.09). Despite some methodological limitations, this research has provided some unique findings that enhance our understanding of AAD use as a fall risk factor. Study findings allow policymakers to further develop evidence-based interventions specific to AADs in order to better manage falls in the PCH setting. However, a great deal of research is still needed to address other important unanswered questions.

Os antipsicóticos são drogas utilizadas no tratamento de muitos transtornos psiquiátricos, sendo classificados em dois grupos: típicos e atípicos. Os típicos formam o grupo de drogas que bloqueiam especialmente os receptores de dopamina e, por isto, causam efeitos colaterais característicos, que se manifestam através de sintomas extrapiramidais e podem terminar em discinesia tardia. Os atípicos apresentam eficácia antipsicótica similar à dos antipsicóticos típicos, mas produzem menos efeitos colaterais extrapiramidais e não causam discinesia tardia. Os antipsicóticos se ligam às proteínas plasmáticas, principalmente a albumina, a qual representa cerca de 60% do total das proteínas no soro humano. Neste trabalho estudamos os processos de interação de duas drogas antipsicóticas atípicas, risperidona e sulpirida, com as albuminas séricas humana (HSA) e bovina (BSA), através da técnica de supressão da fluorescência intrínseca do triptofano. A partir dos espectros de fluorescência, a análise dos dados foi feita obtendo-se os gráficos e as constantes de Stern-Volmer. A análise da supressão da fluorescência foi feita a partir da média aritmética dos dados oriundos dos experimentos realizados em cada condição adotada. Como a molécula da sulpirida é fluorescente desenvolvemos uma modelagem matemática do processo de interação, que nos permitiu então obter os dados referentes à supressão da fluorescência da proteína. Os resultados mostraram que a risperidona e a sulpirida suprimem a fluorescência de ambas albuminas por um processo de quenching estático, formando complexos droga-albumina. A risperidona tem uma afinidade com a HSA cerca de 6,5 vezes maior do que a sulpirida, a 37 oC. As constantes de associação calculadas para a interação risperidona-HSA, através da Teoria de Stern-Volmer, foram 1,43 ( 0,05) x 105 M-1, a 37 C, e 2,56 ( 0,09) x 105 M-1, a 25 C1; e para a sulpirida, 2,20 ( 0,08) x 104 M-1, a 37 C, e 5,46 ( 0,20) x 104 M-1, a 25 C. Como a taxa de quenching da BSA foi maior do que a da HSA, sugerimos que o sítio primário para a risperidona nas albuminas esteja localizado mais próximo ao domínio do triptofano 134 da BSA do que do domínio do triptofano 212 da HSA. O mesmo sugerimos com relação ao sítio para a sulpirida a 37 C. / Antipsychotics are drugs used to treat many psychiatric disorders. They are classified into two groups: typical and atypical. The typical group act blocking dopamine receptors in particular and it causes characteristic side effects with extrapyramidal symptoms, and can lead to tardive dyskinesia. The atypical group presents similar efficacy to typical group, but they produce less extrapyramidal side effects and does not cause tardive dyskinesia. Antipsychotics bind to plasmatic proteins, mainly to albumin, which represents about 60% of total human serum proteins. In this study we studied the interactions of two atypical antipsychotic drugs, risperidone and sulpiride, with human serum albumin (HSA) and bovine (BSA) through the technique of intrinsic tryptophan fluorescence quenching. From the fluorescence spectra, a data analysis was made to obtain Stern-Volmer plots and constants. Quenching analysis was performed used from using arithmetic means of data from experiments for each adopted condition. As sulpiride molecule is fluorescent, a mathematical modeling for interaction process was made. It allows us then to obtain the data referents to fluorescence quenching of protein. Results showed that risperidone and sulpiride quench the fluorescence for both albumins by static quenching process, forming complexes drug-albumin. The risperidone affinity to HSA is about 6.5 higher than supiride, at 37 oC. Stern-Volmer constants for interaction risperidone-HSA were 1.43 ( 0.05) x 105 M-1, at 37oC, and 2.56 ( 0.09) x 105 M-1, at 25 oC; and for sulpiride were 2.20 ( 0.08) x 104 M-1, at 37 oC, and 5.46 ( 0.20) x 104 M-1, at 25 oC. As the quenching ratio for BSA was higher than HAS, we suggested that the primary site for risperidone on albumin is closer of the domain of trypthophan 134 of BSA than the domain of trypthophan 212 of HAS. The same is suggested for the primary site of supiride at 37oC.

Inledning: År 2030 uppskattas det vara ungefär 230 000 stycken människor i Sverige somhar drabbats av någon typ av demenssjukdom. Sjukdomens stadier delas in i begynnande,mild, måttlig och svår demens. Där första symtomen i den begynnande fasen brukar vara attden drabbade inte kommer ihåg vart den lagt sina saker. I den svåra fasen av sjukdomen ärpatienten förmodligen beroende av dygnet runt vård, patienten brukar även ha svårt attprata, enstaka ord eller meningar brukar upprepas. Beteendemässiga och psykiska symtom(BPSD) hos demenssjuka är symtom som kan orsaka lidande hos patienten och dessanhöriga. Symtomen delas in i fyra undergrupper affektiva, psykossymtom, hyperaktivitetoch apati. Riskfaktorn med högst evidens är Apolipoprotein E (ApoE), ApoEε4-allelen.Riskfaktorer med lägre evidensgrad är t.ex. låg utbildning och släktskap. Sjukdomen orsakas av att nervcellerna i hjärnan dör, framförallt i delen av hjärnan därminnet sitter. En röntgen av hjärnan visar onormala proteininlagringar, amyloida plack.Amyloidhypotesen påstår att det blir en överproduktion av amyloid-beta proteinet vilken trosvara den patologiska händelsen vid Alzheimers sjukdom. Tauproteinet hyperfosfyleras till enisoform som är tre gånger större än i en frisk hjärna, om överproduktion av tau på specifikaställen eller hela hjärnan orsakar sjukdomen har forskarna inte kommit fram till ännu. Mildtill måttlig Alzheimers sjukdom behandlas med acetylkolinesterashämmarna donepezil,rivastagmin och galantamin. Svår Alzheimers sjukdom behandlas med en NMDAreceptoragonist,memantin. Syfte: Att undersöka om acetylkolinesterashämmare eller neuroleptika fungerar bäst vidsymtom som uppkommer vid BPSD, samt undersöka vilka biverkningar som är vanligast. Metod: PubMed har använts för att hitta studier som stämmer in på inklusionskriterierna.Studier som exkluderas är de som undersökt fel substans, fel indikation eller fel preparat t.ex.omega-3. Resultat: De vanligaste biverkningarna som rapporterats hos acetylkolinesterashämmarnaär bland annat illamående och kräkningar. Av neuroleptika preparaten verkar det varasömnighet som är den mest rapporterade biverkningen. Studierna som undersökteneuroleptika kom fram till ungefär samma sak, att preparaten kan förbättra symtomen. Av destudier som undersökte acetylkolinesterashämmarna var det tre studier som drog slutsatsenatt de kan ha effekt. En studie säger att det inte sågs någon skillnad mellan donepezil ochplacebo vid dessa typer av symtom. Diskussion: Då de olika studierna som använts i arbetet har undersökt olika effektmått hardet varit svårt att göra en rättvis bedömning om läkemedlen fungerar eller ej. Då i de flestafall bara gått och jämföra ett effektmått från studierna. Hade jag bestämt vilka effektmåttsom fick finnas i varje studie redan från början och sedan gjort en exkludering utifrån det,hade det varit enklare att jämföra studierna och därefter kommit fram till en bra slutsats. Viden jämförelse mellan de olika substanserna ur neuroleptikagruppen, är sömnighet denvanligaste biverkningen i tre av fyra grupper. Viktökning är också en av de vanligastebiverkningarna i två av grupperna där ungefär 32% drabbades av just denna biverkning.Varför patienterna ökat i vikt framgår inte i studierna. Slutsats: Acetylkolinesterashämmare och neuroleptika kan ha effekt vid symtom somuppkommer vid BPSD. Acetylkolinesterashämmarna bör provas i första hand om intebehandlingen redan är insatt.

Abstract Antipsychotic medication forms a cornerstone in the treatment of schizophrenia and its effect on positive symptoms and relapse prevention after the first episode has been shown. After the first episode, the treatment guidelines for schizophrenia recommend the continuation of antipsychotic medication at a minimum from six months to five years. The long-term and life-span benefits and harmful side-effects are not fully known. The aim of this naturalistic study was to analyze long-term use of antipsychotic medication with a special interest in medication tapering and discontinuation in schizophrenia. Non-medicated subjects were more often males and in remission, less often on a disability pension, and had better clinical outcomes when compared to medicated subjects at age 34 years. No differences were found when comparing relapse rates during the 8.7 years of follow-up after 34 years between non-medicated and medicated subjects. Not having been hospitalized during the previous 5 years before the follow-up predicted long-term successful antipsychotic discontinuation without relapse. In the long-term, use of antipsychotic medication became steadier after the first five years. A favorable outcome was associated with low and steady antipsychotic medication, and unfavorable with high long-term cumulative use and antipsychotic polypharmacy. Subjects with antipsychotic medication had non-significantly lower total gray matter (TGM) volume compared with non-medicated subjects. Time without antipsychotic medication preceding magnetic resonance imaging was associated with increased TGM and with increased regional volume in the right precentral gyrus and right middle frontal gyrus. This study has a unique description of long-term use of antipsychotics. It provides new information on medication discontinuation and its effect in schizophrenia in the long-term in terms of relapses and brain morphometry. / Tiivistelmä Psykoosilääkkeet muodostavat perustan skitsofrenian hoidolle, ja niiden on osoitettu tehoavan positiivisiin oireisiin ja relapsin (psykoosin uusiutumisen) estoon ensipsykoosin jälkeen. Skitsofrenian hoitosuosituksissa suositellaan psykoosilääkityksen jatkamista ensipsykoosin jälkeen vähintään puolesta vuodesta viiteen vuoteen. Psykoosilääkityksen pitkäaikaiset ja elämänkestoiset hyödyt ja haittavaikutukset eivät ole täysin tiedossa. Tämän naturalistisen tutkimuksen tavoitteena oli analysoida antipsykoottisen lääkityksen pitkäaikaiskäyttöä ja erityisesti lääkityksen lopettamista skitsofreniassa. Lääkkeettömät tutkittavat olivat 34-vuotiaina useammin miehiä sekä remissiossa (elpymävaiheessa), harvemmin työkyvyttömyyseläkkeellä, ja heillä oli parempi toimintakyky verrattuna lääkkeitä käyttäviin. Lääkkeettömien ja lääkkeitä käyttävien välillä ei havaittu 8,7 vuoden seurannassa eroa relapsien määrissä 34 ikävuoden jälkeen. Psykoosilääkkeiden onnistunutta, pitkäaikaista lopettamista ilman relapsia ennusti seurannassa se, ettei tutkittava ollut ollut sairaalahoidossa seurantaa edeltävien viiden vuoden aikana. Pitkällä aikavälillä psykoosilääkityksen käyttö tasaantui ensimmäisten viiden vuoden jälkeen. Suotuisa ennuste liittyi vähäiseen ja jatkuvaan lääkitykseen. Epäsuotuisa ennuste puolestaan liittyi korkeaan kumulatiiviseen lääkemäärään ja useamman psykoosilääkkeen yhtäaikaiskäyttöön. Lääkkeitä käyttävien tutkittavien harmaan aineen kokonaistilavuus oli ei-merkitsevästi pienempi kuin lääkkeettömien tutkittavien. Psykoosilääkityksetön aika ennen magneettikuvausta oli yhteydessä suurempaan harmaan aineen kokonaistilavuuteen sekä paikallisesti suurempaan tilavuuteen oikeassa etukeskipoimussa ja keskiotsapoimussa. Tämä tutkimus kuvaa ainutlaatuisesti pitkäaikaista psykoosilääkkeiden käyttöä. Se tarjoaa uutta tietoa lääkityksen lopettamisesta ja sen pitkän aikavälin vaikutuksista relapseihin ja aivojen rakenteeseen skitsofreniassa.