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1.
Treatment-Resistant Schizophrenia: Definition, Predictors, and Therapy Options.
Correll, CU, Howes, OD
The Journal of clinical psychiatry. 2021;(5)
Abstract
Treatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence. Several demographic, clinical, and neurologic predictors are associated with TRS. Primary (or early) TRS is present from the beginning of therapy, while patients with secondary (or later-onset) TRS initially respond to antipsychotics but become resistant over time, often after relapses. Guidelines worldwide recognize clozapine as the most effective treatment option for TRS, but clozapine is underused due to various barriers. Importantly, studies indicate that response rates are higher when clozapine is initiated earlier in the treatment course. Side effects are common with clozapine, particularly in the first few weeks, but can mostly be managed without discontinuation; they do require proactive assessment, intervention, and reassurance for patients. Furthermore, plasma leucocyte and granulocyte levels must be monitored weekly during the first 18-26 weeks of treatment, and regularly thereafter, according to country regulations. Therapeutic drug monitoring of clozapine trough plasma levels is helpful to guide dosing, with greatest efficacy at plasma clozapine levels ≥350 µg/L, although this level is not universal. Notably, plasma clozapine levels are generally greater at lower doses in nonsmokers, patients with heavy caffeine consumption, in women, in obese people, in those with inflammation (including COVID-19 infection), and in older individuals. Earlier and broader use of clozapine in patients with TRS is an important measure to improve outcomes of patients with this most severe form of the illness.
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Reduced Jumping to Conclusion Bias after Experimentally Induced Enhancement of Subjective Body Boundaries in Psychosis.
Lyons, N, Dietrich, DE, Graser, J, Juckel, G, Koßmann, C, Krauß, H, Müller, B, Michalak, J
Psychopathology. 2021;(2):92-97
Abstract
INTRODUCTION A disturbed sense of self is frequently discussed as an etiological factor for delusion symptoms in psychosis. Phenomenological approaches to psychopathology posit that lacking the sense that the self is localized within one's bodily boundaries (disembodiment) is one of the core features of the disturbed self in psychosis. The present study examines this idea by experimentally manipulating the sense of bodily boundaries. METHODS Seventy-three patients with psychosis were randomly assigned to either a 10-min, guided self-massage in the experimental group (EG) to enhance the sense of bodily boundaries or a control group (CG), which massaged a fabric ring. Effects on an implicit measure (jumping to conclusion bias; JTC) and an explicit measure (Brief State Paranoia Checklist; BSPC) of delusion processes were assessed. The JTC measures the tendency to make a decision with little evidence available, and the BSPC explicitly measures the approval of paranoid beliefs. RESULTS Patients in the EG showed a lower JTC (M = 4.11 draws before decision) than the CG (M = 2.43; Cohen's d = 0.64). No significant difference in the BSPC was observed. DISCUSSION/CONCLUSION Our results indicate that enhancing the sense of body boundaries through a self-massage can reduce an implicit bias associated with delusional ideation and correspondingly support the idea that disembodiment might be a relevant factor in the formation of psychotic symptoms.
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Second-Generation Antipsychotic Drugs for Patients with Schizophrenia: Systematic Literature Review and Meta-analysis of Metabolic and Cardiovascular Side Effects.
Rognoni, C, Bertolani, A, Jommi, C
Clinical drug investigation. 2021;(4):303-319
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Abstract
BACKGROUND AND OBJECTIVES Second-generation antipsychotics (SGAs) for schizophrenia show different risk profiles, whose evidence has been evaluated through comparative reviews on randomized controlled trials (RCTs) and observational studies. METHODS We performed a systematic review and meta-analysis of weight gains, metabolic and cardiovascular side effects of SGAs, relying on both RCTs and observational studies, by comparing variations between the start of treatment and the end of follow-up. The systematic review refers to papers published from June 2009 to November 2020. PRISMA criteria were followed. No restrictions on heterogeneity level have been considered for meta-analysis. A test for the summary effect measure and heterogeneity (I2 metric) was used. RESULTS Seventy-nine papers were selected from 3076 studies (61% RCTs, 39% observational studies). Olanzapine and risperidone reported the greatest weight gain and olanzapine the largest BMI increase. Paliperidone showed the highest increase in total cholesterol, but is the only drug reporting an increase in the HDL cholesterol. Quetiapine XR showed the highest decrease in fasting glucose. Lurasidone showed the lowest increase in body weight and a reduction in BMI and was also the only treatment reporting a decrease in total cholesterol and triglycerides. The highest increase in systolic and diastolic blood pressure was reported by quetiapine XR. CONCLUSIONS Despite some limitations (differences in the mean dosages per patient and other side effects not included) this paper provides the first complete meta-analysis on SGAs in variations on metabolic risk profile between start of treatment and end of follow-up, with useful results for clinical practice and possibly for future economic evaluation studies.
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Liraglutide does not change bone turnover in clozapine- and olanzapine-treated schizophrenia overweight patients with prediabetes - randomized controlled trial.
Maagensen, H, Larsen, JR, Jørgensen, NR, Fink-Jensen, A, Vilsbøll, T
Psychiatry research. 2021;:113670
Abstract
Schizophrenia is associated with a lowered bone mineral density. The antidiabetic and body weight lowering glucagon-like peptide-1 receptor agonist liraglutide has shown to mitigate overweight and impaired glucose tolerance associated with olanzapine and clozapine. As liraglutide has been proposed to affect bone metabolism, we evaluated the effect of liraglutide on bone turnover markers (BTM) in patients with prediabetes and schizophrenia treated with olanzapine or clozapine. Patients diagnosed with a schizophrenia spectrum disorder treated with the antipsychotic compounds clozapine and/or olanzapine, having prediabetes and a BMI above 27 kg/m2 were randomized to 16 weeks of treatment with liraglutide or placebo. Fasting state serum sampled in the morning from patients (n=78) were analysed for the BTM collagen type 1 C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP). After 16 weeks of treatment, no significant changes of neither P1NP nor CTX were observed when comparing liraglutide to placebo. No association between changes of bone turnover markers and change of body weight were found in the group treated with liraglutide. In conclusion, no treatment effect on CTX nor P1NP was observed, and thus, this study does not raise any concerns in patients with schizophrenia and prediabetes treated with liraglutide regarding bone-related adverse effects.
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Antipsychotic-Induced Constipation: A Review of the Pathogenesis, Clinical Diagnosis, and Treatment.
Xu, Y, Amdanee, N, Zhang, X
CNS drugs. 2021;(12):1265-1274
Abstract
Antipsychotic-induced gastrointestinal hypomotility and, in particular, its manifestation of constipation are common adverse effects in patients with schizophrenia in clinical practice. Serious complications of antipsychotic-induced constipation include ileus, ischaemic bowel disease, colon perforation, aspiration pneumonia, and bacterial septicaemia, which can be life threatening if left untreated, especially in patients prescribed clozapine. The aim of this paper is to review the latest research on the epidemiology, clinical examination methods, pathophysiology, and treatment options and preventive measures for antipsychotic-induced constipation. While clinicians are normally aware of the overall side effects caused by antipsychotics, constipation is often an under-recognized condition despite its relatively high incidence and its impact on daily living. The incidence of constipation differs among individual antipsychotics, but more than 50% of patients prescribed antipsychotics suffer from constipation. Limited fluid intake, poor dietary habits, and a sedentary lifestyle can also worsen constipation. The mechanisms of antipsychotic-induced constipation may be antagonism of cholinergic, histaminergic, and serotonergic receptors, with both parent drug and metabolite(s) contributing to the effects on gastrointestinal motility. Numerous methods, mainly divided into scale evaluations and objective examinations, are applied to evaluate antipsychotic-induced constipation; however, objective examinations have a greater ability to identify cases of gastrointestinal hypomotility since there is often an under-reporting of symptoms in subjective reporting and scale evaluation due to a higher pain threshold, an inability to express pain sensations, and a lack of symptom awareness in these patients. Antipsychotic drug-induced constipation should be closely monitored in patients receiving these medications, with timely intervention to avoid serious gastrointestinal consequences. There is currently no consensus on the efficacy of laxatives in these patients. Further in-depth studies should explore the underlying mechanisms and devise optimal therapeutic approaches to minimize constipation during antipsychotic treatment.
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Does Dysbiosis Increase the Risk of Developing Schizophrenia? - A Comprehensive Narrative Review.
Novais, F, Capela, J, Machado, S, Murillo-Rodriguez, E, Telles-Correia, D
Current topics in medicinal chemistry. 2021;(11):976-984
Abstract
BACKGROUND There is increasing evidence regarding the influence of the intestinal microbiota on the disease processes of various organs and systems. Dysbiosis, that is, alteration of the composition and function of the microbiota may constitute an important risk factor for the development of mental disorders, namely, schizophrenia. OBJECTIVE This works aims to review current evidence regarding the pathological mechanisms leading from dysbiosis to schizophrenia and in particular the deficit syndrome in schizophrenia. METHODS Scientific articles from PubMed, SCOPUS, EMBASE, and Web of Science Core Collection published between September 2017 and December 2020 were included in this review. RESULTS The commensal intestinal flora plays an important role in neurodevelopment. In the presence of dysbiosis, this maturation gets disturbed, resulting in the modification of brain structures and inflammatory responses at the intestinal, systemic, and Central Nervous System (CNS) levels. These disturbances may be linked to the development of symptoms of the disease. The microbiota exerts its influence on the CNS through several pathways, however, in this paper we focused on the membrane hypothesis and the inflammatory hypothesis. We explored the evidence concerning the use of probiotics, prebiotics, and fecal transplants. CONCLUSION Although there is no consensus regarding the alterations that could constitute a risk factor for schizophrenia, some of the species appear to be more frequently altered, and their relationship with the host is dysregulated in patients at risk and with established schizophrenia, particularly in deficit schizophrenia.
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Memantine in neurological disorders - schizophrenia and depression.
Czarnecka, K, Chuchmacz, J, Wójtowicz, P, Szymański, P
Journal of molecular medicine (Berlin, Germany). 2021;(3):327-334
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Abstract
Memantine is used in Alzheimer's disease treatment as a non-competitive modern-affinity strong voltage-dependent N-methyl-D-aspartate receptor antagonist. The fundamental role of these receptors is to bind glutamate: the main excitatory neurotransmitter in the brain, believed to play a crucial role in neuronal plasticity and learning mechanisms. Glutamate transmission plays an important role in all internal CNS structures and maintains the physiological state of the brain. Excessive glutamate transmission can lead to enlarged calcium ion current which may cause neurotoxicity; however, insufficient transmission can drastically alter the information flow in neurons and the brain, potentially causing schizophrenia-like symptoms by replacing lost information with completely new stimuli. Hence, it is possible that the modulation of NMDA activity may give rise to pathophysiological states. Available literature and clinical trials indicate that memantine is well tolerated by patients, with very few and light side effects. There is a belief that memantine may also benefit other conditions such as schizophrenia and depression.
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Targeting the microbiome-gut-brain axis for improving cognition in schizophrenia and major mood disorders: A narrative review.
Bioque, M, González-Rodríguez, A, Garcia-Rizo, C, Cobo, J, Monreal, JA, Usall, J, Soria, V, , , Labad, J
Progress in neuro-psychopharmacology & biological psychiatry. 2021;:110130
Abstract
Cognitive impairment has been consistently found to be a core feature of serious mental illnesses such as schizophrenia and major mood disorders (major depression and bipolar disorder). In recent years, a great effort has been made in elucidating the biological causes of cognitive deficits and the search for new biomarkers of cognition. Microbiome and gut-brain axis (MGB) hormones have been postulated to be potential biomarkers of cognition in serious mental illnesses. The main aim of this review was to synthesize current evidence on the association of microbiome and gut-brain hormones on cognitive processes in schizophrenia and major mood disorders and the association of MGB hormones with stress and the immune system. Our review underscores the role of the MGB axis on cognitive aspects of serious mental illnesses with the potential use of agents targeting the gut microbiota as cognitive enhancers. However, the current evidence for clinical trials focused on the MGB axis as cognitive enhancers in these clinical populations is scarce. Future clinical trials using probiotics, prebiotics, antibiotics, or faecal microbiota transplantation need to consider potential mechanistic pathways such as the HPA axis, the immune system, or gut-brain axis hormones involved in appetite control and energy homeostasis.
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COVID-related psychological distress fully mediates the association from social impact to sleep disturbance among patients with chronic schizophrenia.
Li, DJ, Chou, LS, Chou, FH, Hsu, ST, Hsieh, KY, Wu, HC, Kao, WT, Lin, GG, Chen, WJ, Huang, JJ
Scientific reports. 2021;(1):16524
Abstract
The aims of the current study were to identify factors associated with sleep disturbance and Coronavirus disease-19 related psychological distress (CPD), and to develop a conceptual model to verify the mediating effect of CPD on the association between social impact and sleep disturbance. This study recruited patients with schizophrenia. Factors associated with the level of sleep disturbance and CPD were identified using univariate linear regression, and further selected into a stepwise multivariate linear regression model. Using structural equation modeling, a mediation model was developed to test the mediating effect of CPD on the association between social impact and sleep disturbance. After estimating with the stepwise and bootstrap regression, higher levels of CPD were associated with higher levels of social anxiety and subjects without a regular diet. Sleep disturbance was associated with a higher level of social anxiety, a history of psychological trauma, chronic disease, and those who did not smoke. The final model confirmed the mediating effects of CPD; whereas, the direct effect from social impact to sleep disturbance did not reach statistical significance. The current study manifests the crucial role of CPD on the association between social impact and sleep disturbance, and timely intervention for CPD is warranted.
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Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia.
Al-Nema, MY, Gaurav, A
Current topics in medicinal chemistry. 2020;(26):2404-2421
Abstract
Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.