Influence Of Antipsychotic Treatment Research Articles

MicroRNAs as potential biomarkers for diagnosis of schizophrenia and influence of antipsychotic treatment.

Characterized by positive symptoms (such as changes in behavior or thoughts, including delusions and hallucinations), negative symptoms (such as apathy, anhedonia, and social withdrawal), and cognitive impairments, schizophrenia is a chronic, severe, and disabling mental disorder with late adolescence or early adulthood onset. Antipsychotics are the most commonly used drugs to treat schizophrenia, but those currently in use do not fully reverse all three types of symptoms characterizing this condition. Schizophrenia is frequently misdiagnosed, resulting in a delay of or inappropriate treatment. Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of schizophrenia. The recent studies reviewed included microRNA profiling in blood- and urine-based materials and nervous tissue materials. From the studies that had validated the preliminary findings, potential candidate biomarkers for schizophrenia in adults could be miR-22-3p, -30e-5p, -92a-3p, -148b-5p, -181a-3p, -181a-5p, -181b-5p, -199b-5p, -137 in whole blood, and miR-130b, -193a-3p in blood plasma. Antipsychotic treatment of schizophrenia patients was found to modulate the expression of certain microRNAs including miR-130b, -193a-3p, -132, -195, -30e, -432 in blood plasma. Further studies are warranted with adolescents and young adults having schizophrenia and consideration should be given to using animal models of the disorder to investigate the effect of suppressing or overexpressing specific microRNAs.

The Influence of Antipsychotic Treatment on the Activity of Abzymes Targeting Myelin and Levels of Inflammation Markers in Patients with Schizophrenia.

Catalytic antibodies, or abzymes, are capable of not only binding but also hydrolyzing various proteins. Previously, an increase in the level of myelin basic protein (MBP)-hydrolyzing activity of antibodies was shown in patients with a number of neurological and mental disorders, including schizophrenia. Furthermore, antipsychotic therapy is known to induce a change in cytokine levels in patients with schizophrenia, which affects regulation of the immune response and inflammatory status. This study investigated the influence of typical and atypical antipsychotics on catalytic antibody activity and the 10 major pro- and anti-inflammatory serum cytokine levels. The study included 40 patients with schizophrenia: 15 treated with first-generation antipsychotics and 25 treated with atypical antipsychotics for 6 weeks. It was found that treatment with atypical antipsychotics changed the levels of some pro-inflammatory cytokines. Antipsychotic therapy also caused a significant decrease in MBP-hydrolyzing activity in patients with schizophrenia (p = 0.0002), and associations of catalytic activity with interleukins were observed.

Dynamic functional connectivity and its anatomical substrate reveal treatment outcome in first-episode drug-na\xefve schizophrenia

Convergent evidence has suggested a significant effect of antipsychotic exposure on brain structure and function in patients with schizophrenia, yet the characteristics of favorable treatment outcome remains largely unknown. In this work, we aimed to examine how large-scale brain networks are modulated by antipsychotic treatment, and whether the longitudinal changes could track the improvements of psychopathologic scores. Thirty-four patients with first-episode drug-naïve schizophrenia and 28 matched healthy controls were recruited at baseline from Shanghai Mental Health Center. After 8 weeks of antipsychotic treatment, 24 patients were re-scanned. Through a systematical dynamic functional connectivity (dFC) analysis, we investigated the schizophrenia-related intrinsic alterations of dFC at baseline, followed by a longitudinal study to examine the influence of antipsychotic treatment on these abnormalities by comparing patients at baseline and follow-up. A structural connectivity (SC) association analysis was further carried out to investigate longitudinal anatomical changes that underpin the alterations of dFC. We found a significant symptomatic improvement-related increase in the occurrence of a dFC state characterized by stronger inter-network integration. Furthermore, symptom reduction was correlated with increased FC variability in a unique connectomic signature, particularly in the connections within the default mode network and between the auditory, cognitive control, and cerebellar network to other networks. Additionally, we observed that the SC between the superior frontal gyrus and medial prefrontal cortex was decreased after treatment, suggesting a relaxation of normal constraints on dFC. Taken together, these findings provide new evidence to extend the dysconnectivity hypothesis in schizophrenia from static to dynamic brain network. Moreover, our identified neuroimaging markers tied to the neurobiology of schizophrenia could be used as potential indicators in predicting the treatment outcome of antipsychotics.

Enhanced mitochondrial autophagy (mitophagy) in oligodendrocytes might play a role in white matter pathology in schizophrenia

Disrupted white matter integrity is a typical feature of brain pathologic alterations in schizophrenia, which includes impaired myelination, decreased oligodendrocyte densities, distortion of their spatial distribution and deviations from normal oligodendrocyte cell morphology. While most genes expressed “in the remaining” oligodendrocytes are downregulated in schizophrenia, only a few are upregulated. To the latter group belong prohibitin 2 and DISC 1, which were recently identified as mitochondria-located mitophagy receptors. Their overexpression, together with greatly reduced numbers and densities of oligodendroglial mitochondria and the structurally “normal appearance of the remaining mitochondria” in these cells as reported by Uranova’s group (Uranova et al., 2001, 2004, 2018), point to enhanced mitophagy in oligodendrocytes in schizophrenia, which is possibly even cell protective by preventing apoptosis. Since massive loss of white matter oligodendrocytes is a characteristic feature of schizophrenia, we assume that increased mitophagy is a late event in the development and/or further progression of white matter pathologic changes. Moreover, altered oligodendroglial mitophagy might in part result from antipsychotic treatment. Further studies are clearly needed to substantiate our hypothesis on enhanced mitochondrial autophagy in schizophrenia, whereby the “drug-naïve state” and the possible influence of antipsychotic treatment could be elegantly simulated using animal models of the disease.

42.1 BODY AND MIND: CARDIO-METABOLIC AND IMMUNE FUNCTION IN FIRST EPISODE PSYCHOSIS AND COMPARISON WITH CENTRAL NEUROFUNCTIONAL MEASURES

BackgroundPeople with schizophrenia die on average 15–20 years earlier than the general population, and the mortality gap has grown in recent years. Non-CNS, particularly cardio-metabolic, causes account for the majority of this premature mortality. Abnormalities in the cardio-metabolic and immune system are well established in patients with schizophrenia, but it is unknown if abnormalities are present in people at risk of psychosis and at illness onset prior to antipsychotic treatment, and how they compare to neurofunctional measures. To address this, we conducted a series of meta-analyses and meta-regressions to determine the magnitude and consistency of findings and influence of antipsychotic treatment, exercise and other factors across cardio-metabolic parameters at onset of psychosis.MethodsWe conducted a meta-analysis of peripheral gluco-regulatory, immune and lipid measures and comparison with brain neurofunctional outcomes (including N-acetyl aspartate, gray matter volume and auditory P300 measures) in studies of clinical high risk samples and first episode psychosis, focusing on drug naïve patients. The entire PubMed, EMBase and PsychInfo databases were searched to identify relevant studies. Then we conducted a meta-review statistical comparison of cardio-metabolic and immune function with neurofunctional measures.Results35 studies (>1500 patients and controls) were included in the meta-analyses. Interleukin-6 (g=2.2, p=0.013), and TNF-alpha (g=0.94, p<0.01) levels and fasting insulin and post-challenge glucose levels were elevated with moderate-large effect sizes (g=0.4, p=0.01; g=0.6, p=0.007 respectively) and cholesterol and low density lipoprotein levels were reduced (g=-0.2, p=0.005, and g=-0.22, p=0.001 respectively), whilst triglyceride levels were increased (g=0.14, p<0.05). These findings remained significant in drug naïve patients and after adjusting for the influence of a number of potential confounders (including body mass, exercise levels, smoking). N-acetyl aspartate levels in frontal cortex and auditory P300 amplitude (g=0.83, p<0.0001) were significantly altered in first episode patients relative to controls. The median effect sizes for cardiometabolic dysfunction (g=0.41) was comparable to that of the neurofunctional measures (g=0.42, p>0.3). Moreover, the median effect size for immune alterations (g=1.3) was significantly greater than that for neurofunctional measures (p=0.002).DiscussionWe demonstrate that effect sizes for markers of cardio-metabolic and immune disturbance are comparable in magnitude to those for markers of neurofunctional CNS disturbances from the onset of psychosis, suggesting schizophrenia involves multiple organ systems from illness onset. The three main pathoetiological models by which CNS and non-CNS abnormalities may co-occur in schizophrenia will be discussed. The shared genetic and environmental risk architecture between schizophrenia and cardiometabolic disorders suggests common aspects of pathoetiology.

A role of the immune system in the pathogenesis of schizophrenia

The review addresses immunological aspects of schizophrenia, a multifactor disease caused by genetic factors, innate disorders of the central nervous system (CNS), including the consequences of perinatal hypoxia and infections, and adverse environmental influences. Neuroinflammation as a part of the pathophysiology of schizophrenia is characterized by the higher transcription of CNS inflammatory mediators, excessive activation of microglia, inhibition of glutamatergic receptors that leads to the decrease in the number of cortical synapses and neuronal apoptosis. The authors discuss a role of genetic polymorphisms of cytokine genes, complement system components etc. The literature data on the changes in systemic immune response and imbalance in Th1/Th2 adaptive immune responses are analyzed as well. Some papers showed higher levels of proinflammatory mediators in CSF and blood of patients with schizophrenia that indicated the involvement of blood brain barrier (BBB) dysfunction. The authors present the recent data on BBB dysfunction in schizophrenia and its role in the pathogenesis of the disease, autoimmunity in patients comparing it with immune activation and genetic predisposition. An important and arguable issues about a role of parasite and viral infections in the pathogenesis of schizophrenia, initiation of immune responses and direct impacts on the brain, an influence of antipsychotic treatment on immunity are discussed. In author's opinion, conflicting results of genetic and immunological studies of schizophrenia may be explained by different methodological approaches to selection of patients and healthy controls and the differences in schizophrenia classification.

Nitric oxide in patients with schizophrenia: the relationship with the severity of illness and the antipsychotic treatment

Objectives: Past studies regarding the relationship between nitric oxide and schizophrenia have reported controversial results. Consequently, the aims of this study are i) to analyze the differences in nitric oxide concentration between patients with schizophrenia and healthy controls, ii) to investigate the influence of antipsychotic treatment on nitric oxide, iii) to correlate nitric oxide concentration with severity of illness, and iv) to investigate the relationship between nitric oxide and any personality disorder.Research design and methods: We recruited 24 patients and 24 controls; the sample was divided into three groups of 8 patients, each according to the pharmacological treatment (haloperidol, olanzapine, or risperidone). The severity of illness was assessed by PANSS and personality traits were evaluated by SCID II. A blood sample was taken to assess the plasma concentration of nitrites and nitrates.Results: Patients presented higher nitrate levels than controls (p < 0.05); subjects under olanzapine reported lower nitrate levels than those treated with risperidone (p < 0.05) or haloperidol (p < 0.001). Nitrate levels were correlated with PANSS total score (rho = 0.748; p < 0.001), but not with SCID II scores.Conclusions: Despite the fact that this study found a correlation between PANSS score and nitrate levels, it is unclear whether nitric oxide is related to the severity of schizophrenia, because nitrate levels are also affected by antipsychotic treatment.

P.3.061 The influence of antipsychotic treatment on brain metabolite measures in schizophrenic patients. a proton magnetic resonance spectroscopy study

P.3.061 The influence of antipsychotic treatment on brain metabolite measures in schizophrenic patients. a proton magnetic resonance spectroscopy study

Effects of Haloperidol and Atypical Neuroleptics on Psychomotor Performance and Driving Ability in Schizophrenic Patients

The influence of antipsychotic treatment on the neuropsychological and psychomotor performance of schizophrenic patients is still a subject of investigation. The present study was designed to evaluate the effects of atypical neuroleptics in comparison with a conventional dopamine antagonist neuroleptic (haloperidol) on several dimensions of psychomotor performance (visual perception, attention, reaction time, and sensorimotor performance) considered to be of relevance in evaluating driving fitness. Psychomotor performance was assessed by means of the ART 90, a computerized Act and React Test which is generally used in diagnosis of psychomotor performance. The 49 participating patients were examined at discharge following psychopathological stabilisation; 20 received haloperidol, 29 received an atypical neuroleptic. Our findings demonstrate a remarkably reduced psychomotor performance in the haloperidol-treated group of schizophrenic patients compared with patients treated with atypical neuroleptics. Only 1 (5%) subject passed all subtests without major failures and could be regarded as competent to drive. Among patients with atypical neuroleptics, 7 patients (24%) passed all test parameters without major failures.

The influence of antipsychotic treatment on cortical activations in patients with schizophrenia using functional magnetic resonance imaging

The etiomechanism of psychiatric disorders is still poorly understood. Optogenetically induced changes in neural networks and consequent change of behavior in transgenic animals has provided a novel opportunity to develop animal models of various psychiatric disorders. We hereby propose zebrafish as a model organism based on the premise of its comprehensive similitude with the mammalian brain. The habenula is an evolutionarily conserved bilateral structure located at the interface of diencephalon, basal nuclei and brainstem working as a gateway between cortical-subcortical and brainstem structures. Many studies have suggested master role of habenula in control of adaptive behavior through regulation of brainstem aminergic nuclei. It is thought to function as a switchboard for regulating emotional behavior in conditions facing survival challenges. The dysregulation of the emotional behavior has been at the base of psychiatric disorders and a functional manipulation of specific habenular nuclei using optogenetics combined with incremental levels of stress challenge may prove to be a basic model for the genesis of psychiatric disorders. Conversely, reversing the manipulation, scaling down stress levels, and providing enriched environment may ease psychiatric symptoms. The present article has proposed a hypothesis on the development of a basic zebrafish model for the psychiatric disorders based on this concept. Such a model may be of great help in understanding the common mechanism involved in genesis and progression of various psychiatric disorders. The article has also elaborated on the operational mechanisms and validity of the methodology and has suggested an experimental design for the proposed study model.