Abstract The association between antipsychotics and brain volume changes in schizophrenia is not clear. Previous imaging studies have not examined benzodiazepine use, though it has been linked to cognitive impairment. The aim of this thesis was to examine the association between long-term antipsychotic and benzodiazepine use and brain structures in schizophrenia. Based on a systematic review and meta-analysis of previous studies on long-term antipsychotic use and brain changes in schizophrenia, a higher antipsychotic exposure associated with parietal lobe decrease and basal ganglia increase. Previous data on the topic is very heterogenous and the overall number of studies is small (N=34). Most reported findings were non-significant. In the Northern Finland Birth Cohort 1966, 38 cases with schizophrenia spectrum disorder participated in the longitudinal study at the ages of 24 and 43. In the cross-sectional study, 44 cases with schizophrenia and 35 cases with affective psychoses participated at the age of 43. Structural brain MRI scans were acquired from all participants an data on antipsychotic and benzodiazepine dose was collected using medical records and interviews. Illness severity and antipsychotic/benzodiazepine dose were included as confounders in the analyses. Higher scan-interval antipsychotic dose associated to volume increase in lateral ventricles and higher benzodiazepine dose associated to volume decrease in the caudate nucleus during the 9-year follow-up. In the 43-year study, higher lifetime antipsychotic dose associated to smaller nucleus accumbens volume in schizophrenia. In comparison, higher lifetime benzodiazepine dose associated to larger volumes of total gray matter, cerebral gray matter, and thalamus in affective psychoses. In analyses without illness severity and other medication as confounders, there were several statistically significant associations. It seems that long-term antipsychotic use may associate to structural brain changes in schizophrenia and some associations may be confounded by symptoms and the use of benzodiazepines. These findings underline the importance of taking benzodiazepine use and other confounding factors into account when studying the effects of antipsychotics on the brain. Further studies should focus on how these findings relate to cognition and functioning. / Tiivistelmä Psykoosilääkityksen yhteys skitsofreniassa tapahtuviin aivomuutoksiin on epäselvä. Aiemmat kuvantamistutkimukset eivät ole tutkineet bentsodiatsepiinien käyttöä, vaikka niiden käyttö on yhdistetty heikompaan kognititioon. Tämän tutkimuksen tarkoituksena oli selvittää pitkäaikaisen psykoosi- ja bentsodiatsepiinlääkityksen yhteyttä aivojen rakenteisiin skitsofreniassa. Systemaattisen katsauksen ja meta-analyysin perusteella suurempi psykoosilääkeannos liittyi päälakilohkon tilavuuden pienenemiseen sekä tyvitumakkeiden koon kasvuun skitsofreniassa pitkäaikaisseurannoissa. Aikaisempi kirjallisuus on erittäin heterogeenistä ja tutkimusten kokonaismäärä on pieni (N=34). Suurin osa löydöksistä ei ollut tilastollisesti merkitseviä. Pohjois-Suomen syntymäkohortti 1966 aineistossa 38 skitsofreniaspektrin psykoosia sairastavaa henkilöä osallistui pitkittäistutkimukseen 34 vuoden ja 43 vuoden iässä. Poikkileikkaustutkimuksessa 44 skitsofreniaa ja 24 mielialapsykoosia sairastavaa henkilöä osallistui tutkimukseen 43 vuoden iässä. Pään rakenteellinen magneettikuvaus tehtiin kaikille osallistujille. Tiedot psykoosilääkkeiden ja bentsodiatsepiinien annoksista kerättiin sairauskertomusmerkinnöistä ja haastatteluista. Taudin vakavuus ja psykoosilääkkeiden/bentosidatsepiinien annos huomioitiin sekoittavina tekijöinä. Korkeampi psykoosilääkeannos liittyi aivokammioiden koon kasvuun ja korkeampi bentsodiatsepiiniannos häntätumakkeen koon pienenemiseen 9 vuoden seurannassa. Poikkileikkaustutkimuksessa korkeampi elinaikainen psykoosilääkeannos liittyi pienempään makaavan tumakkeen tilavuuteen skitsofreniassa. Mielialapsykooseissa korkeampi elinaikainen bentsodiatsepiiniannos liittyi suurempaan koko aivojen harmaan aineen, isoaivojen harmaan aineen ja talamuksen tilavuuteen. Kun sekoittavia tekijöitä ei otettu huomioon, tilastollisesti merkitseviä yhteyksiä löytyi useammilta aivoalueilta Tutkimuksen perusteella psykoosilääkkeiden pitkäaikaiskäyttö saattaa liittyä aivojen rakenteellisiin muutoksiin skitsofreniassa. Bentsodiatsepiinien käyttö ja oireet voivat toimia sekoittavina tekijöinä. Löydökset korostavat sekoittavien tekijöiden huomioimisen tärkeyttä tutkittaessa psykoosilääkkeiden vaikutuksia aivoihin. Tulevaisuudessa tutkimusten tulisi selvittää, miten löydökset liittyvät kognitioon ja toimintakykyyn.

Les neuroleptiques ou antipsychotiques sont indiqués dans le traitement des troubles psychotiques et selon les molécules, troubles du comportement et traitement de courte durée de l'anxiété. Depuis l'introduction des neuroleptiques de seconde génération, la prescription s'est étendue à plusieurs utilisations, avec ou sans autorisation de mise sur le marché (AMM). Les travaux de thèse ont pour objectif de décrire le profil des patients et les conditions réelles d'utilisation des neuroleptiques en France, permettant ainsi de vérifier le respect des indications de l'AMM et des recommandations. Nous avons également comparé les effets des neuroleptiques sur la cognition dans une pathologie fréquente (la schizophrénie) à partir d'une méta-analyse en réseau et comparé l'efficacité en conditions réelles des traitements neuroleptiques et apparentés dans une maladie rare avec des symptômes différents (la maladie de Huntington).Nos résultats montrent qu'en population générale, 2,23% de la population avait reçu au moins un neuroleptique. Les médicaments les plus couramment remboursés étaient la cyamemazine, la risperidone, l'olanzapine et l'halopéridol. Une utilisation était inappropriée entre 10 et 31% des patients selon les molécules. Les patients traités par neuroleptiques soit dans le cadre de la schizophrénie soit dans le cadre de la maladie de Huntington, présentaient une évolution différente des scores cognitifs selon le neuroleptique utilisé. Ainsi, c'était une benzamide qui se retrouvait être la classe avec l'effet le plus défavorable sur la cognition. / Antipsychotics are indicated for the treatment of psychotic disorders and according to the drugs, behavioral disorders and short-term treatment of anxiety. Since the introduction of second-generation antipsychotics, prescriptions have extended to several uses, with or without marketing authorization. The thesis aims to describe the profile of patients and the actual conditions of use of antipsychotics in France, and to verify compliance with the indications of the marketing authorization and recommendations. We also compared the effects of antipsychotics on cognition in a common disorder (schizophrenia) with a network meta-analysis and compared the efficacy of antipsychotics and related treatments in real conditions, in a rare disease with different symptoms (Huntington's disease).Our results showed that in general population, 2.23% of the population had received at least one antipsychotic. The most common drugs reimbursed were cyamemazine, risperidone, olanzapine and haloperidol. Inappropriate use was between 10 and 31% of patients depending on the drug. Patients treated with antipsychotics as part of schizophrenia or in the context of Huntington's disease, showed a different pattern on cognitive scores depending on antipsychotic use. Thus, it was found that benzamide was the class with the most adverse effect on cognition.

This study was undertaken to determine adherence rates to side effect monitoring guidelines of second-generation antipsychotics (SGAs) approximately 10 years after their publication to assess the quality of care being provided to patients with mental illness at an urban community mental health center located in the Southeast United States. Results indicated an initial combined collection of fasting blood glucose (FBG) and fasting lipid profile (FLP) of 30%. At the 3-month time point, 20% of FBG and FLP were checked and at 1 year 14%. Study results suggest there is a need for practice improvements to increase quality of care.

Introduction : Dans la population pédiatrique, la prescription des antipsychotiques (AP) connait une hausse majeure ces quinze dernières années malgré une Autorisation de Mise sur le Marché (AMM) française limitée à quelques molécules AP avec des indications réduites. Cela conduit à un taux de prescription hors AMM important avec des modalités de prescription dépendantes du prescripteur en l’absence de recommandations de prescription et de surveillance. De plus, la littérature relève un nombre inquiétant d’événements indésirables (EI) associé à un manque de données sur les conséquences à moyen et long terme. Méthode : L’étude ETAPE nationale, multicentrique, prospective a été financée par l’Agence Nationale de Sécurité du Médicament et des produits dérivés. L’objectif principal était de déterminer le taux d’incidence des EI au cours d’un suivi de 12 mois chez des enfants et des adolescents de 6 à 18 ans exposés pour la première fois à un AP quel que soit le motif de la prescription. Le suivi proposé était de 12 mois avec 5 visites (à l’inclusion, puis à 3, 6, 9 et 12 mois). Une recherche exhaustive des EI a été réalisée à chaque visite grâce à la passation d’échelles cliniques, un examen physique et des bilans complémentaires. Résultats : L’étude a débuté en Avril 2013, la période d’inclusion s’est étendue sur deux ans et le suivi s’est terminé en Avril 2016. Au total, 200 patients ont été inclus. Les données de 190 patients ont été analysées. L’âge moyen était de 12 ± 2,99 ans, avec une proportion de 75% de garçons. A l’inclusion, 91% des patients ont reçu un AP en monothérapie et 9% au moins deux psychotropes. Rispéridone et aripiprazole étaient les AP les plus prescrits. Parmi les prescriptions d’AP, 20,5% répondaient à une AMM. Parmi les EI potentiellement attribuables à l’AP : 15,4% étaient neuromoteurs, 14,8% gastroentérologiques, 12,2% métaboliques et 11,8% étaient des symptômes généraux. Le taux d’incidence des EI était de 11,52 EI par personne-année (IC 95% [9,83 ; 13,20]). Chez les 108 patients avec un suivi complet de 12 mois, 52,7% des EI sont apparus au cours du premier trimestre d’exposition (représentés principalement par les EI généraux et hormonaux). Néanmoins, l’apparition des EI était observée pendant toute la durée du suivi. Parmi ces patients, 25,8 % ont présenté au moins un EI sévère ou extrêmement sévère. De plus, la présence des EI s’est révélée stable au cours des 12 mois. Conclusion : Ce travail a contribué à mettre en évidence dans une population naïve pédiatrique nationale un fort taux d’incidence d’EI et un taux d’apparition et de présence des EI stable sur 12 mois. La présence d’EI sévères a touché un quart de la population ayant complété le suivi. Perspectives : Sur un échantillon de 55 patients niçois nous chercherons l’impact du polymorphisme génétique des cytochromes dans le métabolisme des AP et sur l’apparition des EI. L’ensemble de ces travaux a pour objectif de contribuer à la mise en place de recommandations de prescription et de surveillance des paramètres cliniques, biologiques et électrocardiographiques lors de l’introduction d’un AP en population pédiatrique pour améliorer la balance bénéfice/risque. / Background In France, as in the rest of the world, the off-label prescription of antipsychotics is on the rise in the pediatric population. In the literature, we noticed a significant lack of data on drug safety and adverse events in the naïve pediatric population treated by antipsychotic in the short as well as in the long term. In addition, studies independent of pharmaceutical laboratories are lacking. Method ETAPE Study was a naturalistic prospective multicenter study conducted between April 2013 and May 2016. Type of AP, concomitant treatment, clinical evaluation and AEs were registered at inclusion and 3-, 6-, 9- and 12-months follow up. This trial is registered with ClinicalTrials.gov, number NCT02007928. The main objective was to determine the incidence rate of adverse events (AEs) in the antipsychotic-naïve pediatric population treated by antipsychotic (AP) during a 12-months. Outcomes A total of 190 patients were analyzed. The mean age was 12 ± 2.99 years, with 75% being males. At baseline, 91% of patients received AP monotherapy and 9% received at least two psychotropic drugs. Risperidone and aripiprazole were the most frequently prescribed AP. 20.5% of prescriptions were in label. Among the AEs potentially attributable to AP, 15.4% were neuromotor, 14.8% gastroenterological, 12.2% metabolic and 11.8% general symptoms. The overall incidence rate was 11.52 AE per person-years (IC 95% [9.83; 13.20]). In patients completing completed FU (n=108), 52.7% of AEs appeared during the first 3 months, but onset of AE was noted during the 12-months FU. 25.8 % of patients have been exposed to at least one severe or extreme severity AE. The persistence of AEs was stable during the 12-months FU.Interpretation The high incidence rate of AEs, the severity and the persistence of AEs justify the necessity of clinical and biological follow-up of AEs during at least 12-months of AP treatment.

Cognitive dysfunction is a core characteristic of schizophrenia, which can often persist when other symptoms, particularly positive symptoms, may be improved with drug treatment. The non-competitive NMDA receptor antagonist, phencyclidine (PCP), is a psychomotor stimulant drug that has been shown to induce symptoms characteristic of schizophrenia in humans and animals. The aim of these studies was to use the sub-chronic PCP model in rats to investigate cognitive dysfunction in behavioural tests which have been highlighted as relevance by the MATRICS initiative (MATRICS.ucla.edu). The main tests used were attentional set-shifting, operant reversal learning, and novel object recognition tasks. The pharmacology of antipsychotics was studied in the reversal learning task using receptor selective compounds. Following this, experiments were carried out using in vitro electrophysiology and in vivo microdialysis in an attempt to investigate the mechanisms underpinning the PCP-induced cognitive deficits. The attentional set-shifting task is a test of executive function, the extra-dimensional shift (EDS) phase relates to the ability to shift attention to a different stimulus dimension; this is impaired in patients with schizophrenia. The studies presented in chapter 2 showed that sub-chronic PCP administration impaired attentional set-shifting performance selectively in the EDS phase, a deficit which was significantly attenuated by sub-chronic administration of clozapine and risperidone, but not haloperidol. The effect of PCP was also shown to be more robust in female rats compared to males. A deficit in set-shifting ability was also observed in isolation reared rats. However, the deficits produced by PCP were more robust than the deficit produced by isolation rearing. The reversal learning task is another test of executive function. Chapter 3 reported that sub-chronic PCP administration impairs reversal learning ability in an operant task, as demonstrated by reduced percent correct responding in the reversal phase of the reversal learning task. It was found that a D1 agonist (SKF-38398), a 5-HT1A partial agonist (buspirone), a 5-HT2C antagonist (SB-243213A) and an agonist and positive allosteric modulator of the alpha 7 nACh receptor (PNU-282987 and PheTQS respectively) are able to reverse the sub-chronic PCP-induced deficit in reversal learning. Although many antipsychotics have affinity for muscarinic M1 and histamine H1 receptors, selective agents at these receptors were not able to improve the PCP-induced deficit. In chapter 4, the atypical antipsychotics, clozapine and risperidone, when given alone to naïve rats had no effect on reversal learning. Haloperidol when given to naïve rats impaired performance at the highest dose. Sub-chronic PCP was again found to impair reversal learning performance. Investigative experiments revealed that the 2 min time-out could be important as a cue. Following a double reversal, olanzapine-treated rats lost the ability to switch between the rules, whereas clozapine and risperidone-treated rats could perform the double reversal. Experiments with the extended (15 min) reversal phase could allow the investigation of the time-course effects of antipsychotics or selective compounds. The studies presented in chapter 5 found a reduction in gamma oscillations in the CA3 region of the hippocampus, following sub-chronic PCP treatment (2-5 weeks post treatment) that was paralleled by a deficit in parvalbumin immunoreactive (IR) cell density, at a similar time point (2 weeks post treatment). In contrast, a time-dependent increase in gamma oscillations was observed (6-8 weeks post treatment), at which point parvalbumin IR cell density was unchanged (8 weeks post treatment). Gamma oscillations were unchanged in the prefrontal cortex (PFC) following the PCP treatment regime. Locomotor activity tests were also carried out to ensure that the sub-chronic PCP treatment was successful. In-vivo microdialysis revealed that vehicle-treated rats show an increase in dopamine in the PFC which is selective for the retention trial of the novel object recognition task. PCP-treated rats were unable to distinguish between the novel and familiar objects and the increase in dopamine observed in vehicle rats was absent. As a control experiment it was also shown that sub-chronic PCP did not induce anxiety-like symptoms in the elevated plus maze and open field tests. These studies suggest that sub-chronic PCP induces cognitive deficits in behavioural tasks, and these deficits may be due to GABAergic mediated processes in the hippocampus and dopaminergic dysfunction in the PFC. These behavioural and neurochemical results are concurrent to findings observed in schizophrenia.

No / Antipsychotic drug-induced side effects of weight gain and sexual dysfunction have clinical significance adversely affecting both compliance and morbidity. This study evaluated the effects of haloperidol and the atypical antipsychotic risperidone (0.1¿1.0 mg/kg) on weight gain, food and water intake, the oestrous cycle and uterine weight in female hooded Lister rats. Haloperidol and risperidone treated rats displayed marked weight gain, although only risperidone induced significant increases in food consumption over the 21-day period. Neither haloperidol nor risperidone influenced water consumption. Marked disruption of the oestrous cycle was observed in risperidone- and haloperidol-treated animals (0.5 and 1.0 mg/kg), which was supported by significantly reduced uterine weights. The findings presented here suggest that the weight gain and sexual dysfunction induced by antipsychotics may be modelled in rodents. This model may offer insight into the mechanisms involved in mediation of such side effects.

Yes / Rationale The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. Objective The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. Methods Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for 7 days, followed by a 7-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for 7 days and were then tested in the perceptual set-shifting task. Results PCP significantly (p < 0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p < 0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). Conclusions These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCP-induced cognitive deficit.

Ever since the emergence of the hypothesis that linked the aetiology of schizophrenia with abnormal membrane phospholipids composition, an increasing number of evidences have suggested reduced membrane polyunsaturated fatty acids in patients with schizophrenia. This has led to a conduct of several studies to evaluate the efficacy of omega-3 fatty acid supplement in the modification of membrane phospholipids and treatment of schizophrenia. The two main omega-3 fatty acid classes, EPA and DHA, play a vital role in membranes. This project work reviews omega-3 fatty acid studies and summarizes their outcomes. Eight original articles (nine studies) were reviewed. Six out of nine studies measured RBC membrane fatty acids levels and all six studies reported a significant increase in EPA after EPA supplement. Two studies reported increased DHA post omega-3 fatty acid and DHA supplement, respectively. One study observed a dose-dependent increment in DHA after EPA supplement. Improved symptoms were observed in seven studies, while one study found a worsening of symptoms in patients with low baseline PUFA. Moreover, out of the six studies that evaluated the correlation between symptom change and membrane fatty acids change, three studies observed a correlation between increased EPA and symptom improvement. One study reported an increased AA associated with improved symptoms, in contrast to another study, which found a correlation between increased AA and worsened symptoms. The conclusion from this project work is that EPA supplement can increase the EPA levels in membranes; however, its therapeutic effect in schizophrenia requires further investigation using larger studies. / Ända sedan tillkomsten av hypotesen som länkade etiologin av schizofreni med onormala sammansättningar av membranfosfolipider, har bevis för nedsatt membranfettsyror hos patienter med schizofreni ökat. Detta har lett till genomförandet av flera studier för att utvärdera effekten av omega-3 supplement i modifieringen av membranfosfolipider och i behandling av schizofreni. De två viktigaste omega-3 klasserna, EPA och DHA, spelar en viktig roll i membran. Detta projektarbete granskar de omega-3 studierna och sammanfattar deras resultat. Åtta originalartiklar (nio studier) granskades. Sex av nio studier mätte nivåer av RBC membranfettsyror och alla sex studierna rapporterade en signifikant ökning av EPA efter EPA behandling. Två studier rapporterade ökad DHA efter omega-3 och DHA behandling, respektive. En studie observerade en dosberoende ökning i DHA efter EPA behandling. Förbättrade symtom observerades i sju studier, medan en studie fann en försämring av symtom hos patienter med låg baseline PUFA. Av de sex studier som utvärderade sambandet mellan symtomförändring och förändring i membranfettsyror, hittade två studier samband mellan ökad EPA och symtomförbättring. En studie rapporterade en ökad AA i samband med förbättrade symtom, i motsats till en annan studie, som fann ett samband mellan ökad AA och försämrade symtom. Slutsatsen från detta projektarbete är att EPA tillägg ökar nivåer av EPA i membranfosfolipider; men dess terapeutiska effekt vid schizofreni kräver ytterligare utredning med hjälp av större studier.

Diese Arbeit beschreibt Ergebnisse einer in-vitro Untersuchung der Antipsychotika Chlorpromazin, Haloperidol, Clozapin, N-Desmethylclozapin und Quetiapin bezüglich ihrer Wirkung auf die Zytokinproduktion. Dafür wurde Vollblut von gesunden Probandinnen invitro mit dem Immunmodulator Toxic-Shock-Syndrome-Toxin-1 (TSST-1) stimuliert. Dabei wurden die Konzentrationen der Zytokine Interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-17 und Tumornekrosefaktor-α (TNF-α) im unstimulierten Blut und im stimulierten Blut, jeweils mit und ohne Zusatz der Antipsychotika gemessen. Es zeigte sich, dass TSST-1 eine signifikante Stimulation der Produktion aller getesteten Zytokine bewirkte und dass es über diese Stimulation mit TSST-1 hinaus zu einer Erhöhung von IL-17 unter allen getesteten Antipsychotika kam. Aufgrund dieser Ergebnisse ist es denkbar, dass Antipsychotika, in Ergänzung zu ihrer Wirkung an Dopaminrezeptoren, auch über diese immunologische Eigenschaft Wirkungen und Nebenwirkungen entfalten können. Weiterhin könnte die IL-17-Produktion ein Biomarker in der Behandlung mit Antipsychotika sein, der wiederum zur individuellen Vorhersage von Wirkungen und Nebenwirkungen beitragen könnte.

Aim: Antipsychotic medication is the predominant intervention used for psychosis in the UK. However, there are risks associated, it is not always effective and service-users express ambivalence towards taking it. The research aims to explore community mental health professionals’ perspectives on working with people with psychosis who express antipsychotic ‘medication refusal’. Method: A mixed-methodology was utilised. A survey of community mental health professionals was undertaken (N=74) to enquire about frequency of medication refusal and actions taken by professionals. Four uni-professional focus-groups were held to discuss the topic. The resulting data was subjected to a discursive analysis. Findings: Antipsychotic medication refusal was presented as a common experience by participants, with service-users often stopping against advice. A substantial proportion of survey participants reported experience of supporting service-users without using antipsychotics or to come off, with good rates of success. ‘Risk talk’ was a prevalent feature of the focus-groups: a range of ‘risk’ repertoires were drawn on by participants to warrant particular actions. Implications: Government initiatives relating to service-user choice, empowerment and recovery in mental health are in opposition to more pervasive ‘risk’ discourses. The notion of ‘risk’ in relation to antipsychotics needs further consideration, with professionals made more aware of its social construction and alternative conceptualisations of psychosis and antipsychotics.