losartan-potassium and Schizophrenia

The pharmacological treatment of schizophrenia is currently based on the employment of antipsychotic medications showing an antagonism of dopaminergic and serotoninergic inhibitors. 20-40% of patients are drug-resistant or residually symptomatic in the long-term antipsychotic treatment, and new strategies are needed for improving their functional and cognitive impairment.. This systematic review has summarized evidences from the literature regarding the newer pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE, The Cochrane Library, and Google Scholar.. The possible role of glutamate and its receptors as targets of the antipsychotic mechanism of action has been described. Glutamatergic neurotransmission and NMDA receptors hypofunction are involved in the neurobiological explanatory model of psychosis and possibly targeted for the successful treatment of cognitive and residual symptoms. Results show an efficacy of D-cycloserine (antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of schizophrenia as well as Memantine (NMDA- Receptor antagonist) for cognition and psychopathology. The putative antipsychotic effect of cannabidiol on positive symptoms and cognition will also be discussed. The action on serotoninergic and GABAergic receptors will be considered as a new pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline has shown to induce improvements in cognitive symptoms in schizophrenia, as well as Erythropoietin. Oxytocin has been reported to have an antipsychotic-like effect; moreover, COX-2 inhibitors lead to a reduction in positive symptoms of psychosis, specifically in the first episode of illness.. This narrative report suggests a promising role of new agents in the treatment of Schizophrenia; however, more research is needed to approve their clinical employment.

Topics: Antipsychotic Agents; Cyclooxygenase 2 Inhibitors; Erythropoietin; Glutamic Acid; Heterocyclic Compounds, 4 or More Rings; Humans; Minocycline; Molecular Targeted Therapy; Oxytocin; Receptors, N-Methyl-D-Aspartate; Schizophrenia

The purpose of this study is to systematically review the efficacy and safety of adjunctive erythropoietin (EPO) in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression based on randomized controlled trials (RCTs).. Two evaluators independently and systematically searched and selected studies, extracted data, and conducted quality assessment.. Four RCTs with 144 patients (71 in the EPO group and 73 in the placebo group) met the study entry criteria. Adjunctive EPO could improve schizophrenia-related cognitive performance. In patients with bipolar disorder, EPO could also enhance sustained attention, recognition of happy faces, and speed of complex information processing across learning, attention, and executive function when compared with placebo. In addition, EPO could enhance verbal recall, recognition, and memory in patients with major depression.. This preliminary study found that adjunctive EPO appears to be effective in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression without major adverse effects observed. Further higher quality RCTs with larger samples are needed to confirm the findings.. CRD42017058094.

Topics: Bipolar Disorder; Cognition Disorders; Depressive Disorder, Major; Erythropoietin; Humans; Randomized Controlled Trials as Topic; Schizophrenia

Cognitive dysfunction is a core feature in a range of neuropsychiatric disorders which reduces patients' workforce capacity - the largest socio-economic cost of these disorders. Nevertheless, there is no clinically available medical treatment with robust and enduring efficacy on cognitive deficits in most neuropsychiatric conditions. Recent research has shown that erythropoietin may have beneficial effects on cognitive dysfunction across neuropsychiatric disorders, including bipolar and unipolar disorders, schizophrenia, Parkinson's disease and multiple sclerosis.

Topics: Bipolar Disorder; Cognition; Cognitive Dysfunction; Erythropoietin; Humans; Mood Disorders; Multiple Sclerosis; Parkinson Disease; Schizophrenia

Schizophrenia is a brain disorder associated with subtle, but replicable cerebral volume loss mostly prevalent in frontal and temporal brain regions. Post-mortem studies of the hippocampus point to a reduction of the neuropil constituting mainly of synapses associated with changes of molecules mediating plastic responses of neurons during development and learning. Derived from animal studies interventions to enhance neuroplasticity by inducing adult neurogenesis, synaptogenesis, angiogenesis and long-term potentiation (LTP) were developed and the results translated into clinical studies in schizophrenia. Out of these interventions aerobic exercise has been shown to increase hippocampal volume, elevate N-acetyl-aspartate in the hippocampus as neuronal marker, and improve short-term memory in schizophrenia. The hematopoietic growth factor erythropoetin (EPO) is involved in brain development and associated with the production and differentiation of neuronal precursor cells. A first study demonstrated a positive effect of EPO application on cognition in schizophrenia patients. In randomised controlled studies with small sample size, the efficacy of repetitive transcranial magnetic stimulation (rTMS), a biological intervention focussing on the enhancement of LTP, has been shown for the improvement of positive and negative symptoms in schizophrenia,. The putative underlying neurobiological mechanisms of these interventions including the role of neurotrophic factors are outlined and implications for future research regarding neuroprotection strategies to improve schizophrenia are discussed.

Topics: Animals; Erythropoietin; Exercise; Humans; Neuronal Plasticity; Schizophrenia; Transcranial Magnetic Stimulation

This systematic review summarizes and critically appraises the literature on the effect of erythropoietin (EPO) in schizophrenia patients and the pathophysiological mechanisms that may explain the potential of its use in this disease. EPO is mainly known for its regulatory activity in the synthesis of erythrocytes and is frequently used in treatment of chronic anemia. This cytokine, however, has many other properties, some of which may improve the symptoms of psychiatric illness. The review follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement guidelines. Three databases (Medline, Web of Science, and Cochrane) were searched combining the search terms 'erythropoietin AND (psychotic disorders OR schizophrenia)'. Seventy-eight studies were included in qualitative synthesis, a meta-analytic approach being prohibited. The findings suggest that several EPO cerebral potential properties may be relevant for schizophrenia treatment, such as neurotransmission regulation, neuroprotection, modulation of inflammation, effects on blood-brain barrier permeability, effects on oxidative stress and neurogenesis. Several potentially detrimental side-effects of EPO therapy, such as increased risk of thrombosis, cancer, increased metabolic rate and mean arterial blood pressure leading to cerebral ischemia could severely limit or halt the use of EPO. Overall, because the available data are inconclusive, further efforts in this field are warranted.

Topics: Blood-Brain Barrier; Cognition Disorders; Erythropoietin; Humans; Inflammation; Neurogenesis; Neuroprotective Agents; Oxidative Stress; Schizophrenia

The growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, anti-apoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

Topics: Animals; Brain Diseases; Erythropoietin; Humans; Nervous System; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Peripheral Nerves; Receptors, Erythropoietin; Retinal Diseases; Schizophrenia; Signal Transduction; Spinal Cord Injuries; Stroke

With the increased life expectancy in western industrialized countries, the incidence and prevalence of brain diseases dramatically increased. Stroke and a wide spectrum of neuropsychiatric illnesses such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic head injury, and schizophrenia all lead to severe disability. However, targeted effective therapies for treatment of these diseases are lacking. Even more frustrating is the fact that we do not yet clearly understand the basic mechanisms underlying the disease processes in these conditions. We propose a hypothesis of loss of neuronal function via a final common deleterious pathway in this clinically very heterogeneous disease group. This review presents a novel neuroprotective concept for treatment of brain disease: Erythropoietin (EPO). EPO is a natural body-own-protein hormone that has been used for treatment of anemia for more than a decade. The neuroprotective approach using EPO in brain disease represents a totally new frontier. The "Göttingen EPO-stroke trial" represents the first effective use in man of a neuroprotective therapy in an acute brain disease while the experimental EPO therapy to combat cognitive decline in patients with schizophrenia will be introduced as an example of a neuroprotective strategy for a chronic brain disease.

Topics: Animals; Brain Diseases; Clinical Trials as Topic; Erythropoietin; Humans; Nerve Degeneration; Neuroprotective Agents; Regeneration; Schizophrenia; Stroke

Topics: Brain; Drug Therapy, Combination; Erythropoietin; Genetic Predisposition to Disease; Humans; Neuroprotective Agents; Neurosciences; Recombinant Proteins; Schizophrenia

Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.

Topics: Adult; Analysis of Variance; Atrophy; Attention; Brain; Double-Blind Method; Erythropoietin; Humans; Male; Memory; Middle Aged; Neuroprotective Agents; Recombinant Proteins; Schizophrenia; Treatment Outcome

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

Topics: Adult; Chronic Disease; Cognition; Cognition Disorders; Erythropoietin; Follow-Up Studies; Humans; Male; Middle Aged; Nerve Growth Factors; Neuronal Plasticity; Placebo Effect; Recombinant Proteins; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Schizophrenia; Treatment Outcome

Erythropoietin (EPO) improves cognitive performance in clinical studies and rodent experiments. We hypothesized that an intrinsic role of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations of EPO and EPO receptor (EPOR) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short-term memory readouts, with one particular combination of genotypes superior to all others (p < 0.0001). In an independent healthy control sample (N > 800), these associations were confirmed. A matching preclinical study with mice demonstrated cognitive processing speed and memory enhanced upon transgenic expression of constitutively active EPOR in pyramidal neurons of cortex and hippocampus. We thus predicted that the human genotypes associated with better cognition would reflect gain-of-function effects. Indeed, reporter gene assays and quantitative transcriptional analysis of peripheral blood mononuclear cells showed genotype-dependent EPO/EPOR expression differences. Together, these findings reveal a role of endogenous EPO/EPOR for cognition, at least in schizophrenic patients.

Topics: Adolescent; Adult; Aged; Animals; Case-Control Studies; Cerebral Cortex; Cognition; Demography; Erythropoietin; Female; Genetic Association Studies; Genetic Predisposition to Disease; Hippocampus; Humans; Male; Memory; Mice; Middle Aged; Neurons; Phenotype; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Pyramidal Cells; Receptors, Erythropoietin; Schizophrenia; Young Adult

Executive function impairment, as classically assessed using the Wisconsin Card Sort Test or intradimensional/extradimensional tests, is a key feature of schizophrenia but remains inadequately treated by existing therapies. Recently, however, erythropoietin has been shown to improve attentional set-shifting performance in schizophrenic patients.. The present study utilized the rat intradimensional/extradimensional task to investigate the potential of erythropoietin to reverse a phencyclidine-induced extradimensional shift impairment when given alone or in combination with subchronic haloperidol treatment.. Rats were subjected to a subchronic systemic administration (7 days, b.i.d) of either saline vehicle or phencyclidine (5 mg/kg) followed by a 7-day washout period during which haloperidol was given. Subsequently, rats were trained to dig in baited bowls for a food reward and to discriminate on the basis of digging media or bowl odor. In experiment 1, rats performed a series of discriminations following acute administration of vehicle, erythropoietin, or modafinil. In a second experiment, rats receiving either haloperidol in the drinking water or just normal drinking water were run in the attentional set-shifting task after acute administration of erythropoietin (1,000 or 10,000 IU/ml  i.p., selected from experiment 1).. The subchronic phencyclidine-induced extradimensional deficit was ameliorated by both erythropoietin and modafinil. When combined with subchronic haloperidol, the higher dose of erythropoietin tested was able to reverse the extradimensional shift impairment.. Overall, these findings further support the use of erythropoietin as an adjunct to antipsychotic therapy in order to address, at least part of, the cognitive dysfunction associated with schizophrenia.

Topics: Animals; Antipsychotic Agents; Attention; Behavior, Animal; Benzhydryl Compounds; Discrimination, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Executive Function; Haloperidol; Male; Modafinil; Neuropsychological Tests; Phencyclidine; Rats; Recombinant Proteins; Reward; Schizophrenia; Schizophrenic Psychology