Browsing by Subject "schizophrenia"

Aims: Schizophrenia is characterized by cognitive impairment that associates with many problems in everyday life and functioning. Earlier research has hypothesized that antidepressant medication may associate with better cognitive functioning among schizophrenia patients, but empirical results are mixed. This study explored the profile of schizophrenia patients that use antidepressants and asked whether there is an association between antidepressant use and cognitive performance in a clinical patient sample. Because of effects on the central nervous system, benzodiazepines and anticholinergic medications were also considered. Methods: Study participants were drawn from the SUPER-Finland cohort, which was collected among patients with psychotic illnesses in 2016–2018 from all university hospital districts across Finland (n=10474). The analysis included working-age (18–70) patients with a schizophrenia diagnosis (F20) and complete results from the brief cognitive assessment (n=3411). Information about regular medications and psychosocial factors were gathered through questionnaire and interview. Cognition was assessed with CANTAB (Cambridge Neuropsychological Test Automated Battery), out of which the subtests measuring reaction time (RTI) and visual learning (PAL) were included. The association of antidepressants on cognition was examined using both pooled antidepressants and various antidepressant groups as predictors in linear regression models. Gender, age, age of diagnosis, living status, relationship, education, and psychological distress were controlled in the models. Results: Over 35% of schizophrenia patients regularly used at least one antidepressant. On average, schizophrenia patients using antidepressants experienced lower well-being and more psychological distress than patients without antidepressants. The use of antidepressants was not generally associated with better or poorer cognitive performance. However, the use of SNRI antidepressants was associated with a significantly faster reaction time. The use of benzodiazepines was associated with poorer cognitive performance in both reaction time and visual learning. Conclusions: The results support the conclusion that there is generally no meaningful association between antidepressants and better cognitive performance in schizophrenia. However, the association of SNRI-medicines with a slightly faster reaction time is promising and warrants further research. Several psychosocial factors were associated with the cognitive performance of schizophrenia patients, which underlines the need for supporting psychosocial well-being in cognitive rehabilitation.

Schizophrenia is a debilitating psychiatric disorder associated with reduced life expectancy. The biological mechanism of schizophrenia is nebulous; however, many findings point to the central nervous system and neurons, where a reduction in dendritic spines has been indicated by previous research. The genetic findings support the involvement of synapses in the pathogenesis of schizophrenia. To study the biological properties stemming from genetics, relevant model systems and efficient methods are needed. Induced pluripotent stem cell (iPSC) technology offers a robust method for modeling the biological processes underlying schizophrenia. Somatic cells, e.g. fibroblasts, can be reprogrammed back to a pluripotent state resembling embryonic stem cells, and further differentiated into any cell type of the body, which might not be otherwise accessible. This allows establishing and characterizing neuronal cultures from patient and control cell lines, potentially revealing biological differences associated to the disease phenotype. The field of schizophrenia research has adopted iPSC technology and multiple studies have been conducted. These include assessments of synaptic density in the produced neuronal cultures, many of which reported decreased density associated with schizophrenia. In this thesis, a modified version of Nehme et al. (2018) protocol was used to differentiate iPSCs into neurons in co-cultures with human iPSC-derived astrocytes. The overarching aim was to construct an immunocytochemistry (ICC) -based assay to measure synaptic density in the produced co-cultures. First, suitable markers for characterization by ICC were tested and selected. The markers were selected to inform about neuronal identity, maturity, and synapses of the differentiated neurons. Next, the culturing conditions were optimized regarding the cell density and coating of the culturing wells. Finally, to estimate the utility of the assay, a pilot study was performed with three cell lines derived from a healthy control and a monozygotic twin pair discordant for schizophrenia. iPSCs from these cell lines were differentiated into neurons in co-cultures with astrocytes, and then characterized with ICC using selected markers and image analysis software. The synaptic density was quantified for each cell line. The performance of the assay was evaluated with analysis of variance (ANOVA) and restricted maximum likelihood model (RELM). An assay to quantify synaptic structures in mature neurons was established. The average synaptic density for all cell lines was approximately 1 synapse per 100μm of neurite. Analysis of the data produced with the assay revealed a notable batch effect and technical variation. This suggests that further optimization is needed to reduce variance from undesired sources. The pilot data suggests that the differences in synaptic density between cases and controls may be modest, further highlighting the need for minimizing noise in the assay to improve signal to noise ratio. However, indicated by power analysis, large sample sizes are needed to identify meaningful differences between cases and controls. In light of these results, more attention should be drawn to the methodology in the field of iPSC-based studies, as the principals of the assay constructed here were similar to other synaptic assays used in previous publications.

Neuronal nicotinic receptors are widely expressed throughout the brain and they facilitate fast synaptic neurotransmission. They are also involved in regulation of the release of other neurotransmitters like GABA, dopamine and glutamate. The most common subtypes are alfa4beta2 and alfa7 subunits containing receptors. Neuronal nicotinic receptors are involved in nicotine addiction but also in many neurological diseases like Alzheimer's disease, schizophrenia, depression and attention deficit/hyperactivity disorder. The cholinergic stimulation enhances cognition in vivo and in human. There is not many drugs on the market that act via nicotinic receptors but many drug companies have new nicotinic agonists and antagonist under clinical research. When using nicotinic receptor agonists the problem is desensitization, which occurs in alfa7 nicotinic receptor rapidly after agonist exposure. When desensitized the receptor no longer responds to agonist even if it is there available to bind to receptor. The desensitization may lead to tachyphylaxis and losing of the clinical effect. Conventional agonists, like acetylcholine, bind to the binding site located in the extracellular part on nicotinic receptor subunit. There is also some other binding sites, which are called allosteric binding sites. It has been found out, that allosterically binding ligands, for example PNU-120596, can cause potentiation of agonist induced responses and/or prevent desensitization of receptor. These kinds of agents are called positive allosteric modulators and they are considered to be a new therapeutic option for CNS diseases containing cholinergic deficits. The mechanism of action of positive allosteric modulators is so far unclear. The purpose of my study was to characterize positive allosteric modulators on alfa7 nicotinic receptor. It had been found out earlier in the Millar laboratory that mutation L247T in the transmembrane domain converts positive allosteric modulators to agonists. The aim was to use site-directed mutagenesis to generate mutation in the agonist-binding site of alfa7 and alfa7L247T receptors and see how it effects on the ability of PNU-120596 to act as an agonist on the receptor. Second aim was to generate a mutation in the transmembrane part of the receptor to an assumed binding site of allosteric potentiators' and test how it effects on allosteric potentiator's ability to act as an agonist on the alfa7L247T. Mutated receptors were expressed on oocytes by microinjeting the mRNA into oocyte. The function of receptors was studied with electrophysiology using two-electrode voltageclamp technique. All the mutations were successfully inserted in nicotinic receptor alfa7 and alfa7L247T. Mutation in orthosteric agonist binding site had a very profound effect on wild type alfa7 receptor; it had an effect on either acetylcholine binding or receptor gating. It was not possible to record any proper responses neither with acetylcholine nor with PNU-120596. In the double-mutated receptor alfa7W149M/L247T the W149M mutation had a much greater effect on dose-response curves than it had on PNU-120596 curves compared with alfa7L247T. The transmembrane domain mutation M253L did not have much effect on PNU-120596's ability to act as an agonist to alfa7L247T and either it did not effect on acetylcholine dose-response curves. The results from this study support the previous results that the binding site of positive allosteric modulators is located in the transmembrane domain of the alfa7 receptor. The results are little controversial with the M253L mutation but because the L247T mutation has so profound effect on the function on alfa7 receptor it might be that it masks the other mutation which is located quite close to it. On the other hand it might be so that the amino acid M253 has only effect on the receptor's ability to be potentiated not the allosteric binding.

Schizophrenia (SZ) is a neurodevelopmental psychiatric disorder with high heritability. Patients with SZ commonly suffer from sleep problems of different types, some of them with potential underlying abnormalities in sleep oscillations. These changes in sleep are usually accompanied by deficits in cognitive performance. However, the relationship between sleep, cognitive performance and genetic risk factors are not well known in SZ. In this study, patients were selected from a nation-wide SUPER -cohort. Sleep and circadian rhythm of patients with SZ (n = 26) and age-matched healthy controls (n = 11) were followed for a week with actigraphy and sleep diary, combined with word-pair -memory task and polysomnography at the end of the week. The results showed that patients spend more time in lighter sleep and awake during the night than controls. As expected, patients had impaired sleep spindle density compared to controls. Additionally, patient had worse overnight memory consolidation. However, sleep spindle density was not associated with memory performance. Lastly, polygenic risk score (PRS) for long sleep, but not PRS for SZ, predicted lower spindle density in patients, which could be indirect evidence for deviated neurophysiological processes of sleep behind the observed deviations in EEG oscillations among the patients. These results show that, as compared to controls, patients with SZ demonstrate abnormalities in their sleep, which can be seen both in macro- and microstructures of sleep. Further analyses of the interplay between sleep oscillations and genetic risk factors are likely needed to link sleep problems with overnight memory consolidation.

A high birth weight (HBW) has quite recently been associated with an increased schizophrenia risk, but the link between a low birth weight (LBW) and schizophrenia is well-known. The purpose of this study was to analyze obstetric adversities – with the focus on the role of HBW - among 109 subjects chosen from the Finnish schizophrenia family study sample. The subjects had a schizophrenia-spectrum disorder or a genetically high risk of developing such a disorder. HBW (≥4000 g, n=37), compared to normal birth weight, NBW (2600-3999, n=64), associated with post-term pregnancy (p=0.041) and higher maternal parity (p=0.017). Post-term pregnancy associated with labour complications (p=0.04) and a prolonged first stage of labour (p=0.003). A higher parity was associated with Caesarean section (p=0.009), prematurity (p=0.048) and fetal malpresentation (p=0.021). LBW (<2600 g, n=8), compared to NBW, associated with perinatal complications (p=0.017), twin pregnancy (p=0.002), prematurity (p=0.009) grand multiparity (p=0.019) and higher parity (p=0.002).