Materiały źródłowe

• #1 Neurobiology of Schizophrenia: A Comprehensive Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9080788/

  Schizophrenia is a debilitating disease that presents with both positive and negative symptoms affecting cognition and emotions. […] There is evidence of significant genetic etiology involving multiple genes such as dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1). […] However, studies have shown that subcortical dopamine dysfunction is the key mechanism. […] The pathophysiology of schizophrenia is complex, and it has been studied for years with many factors yet to be discovered. Genetic studies show that schizophrenia involves different genetic loci and is highly pleiotropic. […] Among all neurotransmitters involved in the pathophysiology of schizophrenia, dopamine plays a major role in psychosis. […] The primary positive, negative, and cognitive symptoms of schizophrenia have been associated with many neurotransmitters, but the subcortical dopamine dysfunction remains to be the key factor in psychotic symptoms.

• #2 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Schizophrenia, a serious mental illness, affects 1% of the global population and is marked by hallucinations, delusions, disorganized speech, grossly disorganized behavior, and negative signs and symptoms such as reduced emotional expression, avolition, and cognitive impairment. […] Causes include genetic, environmental, and neurobiological factors. No single gene is responsible; there is an interplay of multiple genetic factors. Environmental influences include prenatal and obstetrical risks, psychosocial stressors, and cannabis use. Neurobiologically, schizophrenia is associated with neurotransmitter dysfunction in dopamine and glutamate systems, as well as brain structural changes. […] The disorder’s etiology and pathophysiological mechanisms remain elusive due to its complexity and heterogeneity.

• #3 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Multifaceted interactions between genetic and environmental risk factors give rise to schizophrenia. These risk factors also affect early brain development and shape the biological response to life experiences, thereby influencing the onset and progression of the disorder. […] Twin and family studies indicate that genetic factors can explain approximately 80% of the risk for schizophrenia. […] Genome-wide association studies have identified 130 genes predominantly associated with neural differentiation, organization, and transmission, which increase the risk of schizophrenia. […] Notably, nearly 30% of these genes are involved in the functioning of the presynaptic and postsynaptic elements of the glutamatergic synapse by impacting N-methyl-D-aspartic acid (NMDA) receptor transmission.

• #4 Schizophrenia pathophysiology: are we any closer to a complete model? | Annals of General Psychiatry | Full Text

  https://annals-general-psychiatry.biomedcentral.com/articles/10.1186/1744-859X-8-12

  Schizophrenia, a severe brain disorder that involves hallucinations, disordered thinking and deficiencies in cognition, has been studied for decades in order to determine the early events that lead to this neurological disorder. […] In addition, current data suggests neurodevelopmental or environmental causes such as viral infections and prenatal/perinatal complications. […] A number of models have been proposed to explain the mechanism for the development of schizophrenia in terms of the nature, timing and the course of brain changes; processes which are still not well understood. […] In order to improve treatment options and prognostic outcomes for schizophrenia it is necessary to understand the pathophysiology that contributes to this disease state. […] Based on early studies, it was believed that the structural brain changes that occur in schizophrenia were caused by early prenatal or perinatal insults, which can present a predisposition to the development of schizophrenia.

• #5 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Multifaceted interactions between genetic and environmental risk factors give rise to schizophrenia. These risk factors also affect early brain development and shape the biological response to life experiences, thereby influencing the onset and progression of the disorder. […] Twin and family studies indicate that genetic factors can explain approximately 80% of the risk for schizophrenia. […] Genome-wide association studies have identified 130 genes predominantly associated with neural differentiation, organization, and transmission, which increase the risk of schizophrenia. […] Notably, nearly 30% of these genes are involved in the functioning of the presynaptic and postsynaptic elements of the glutamatergic synapse by impacting N-methyl-D-aspartic acid (NMDA) receptor transmission.

• #6 Schizophrenia Pathogenesis and Clinical Findings | Calgary Guide

  https://calgaryguide.ucalgary.ca/schizophrenia-pathogenesis-and-symptoms/schizophrenia-pathogenesis-and-clinical-findings/

  Schizophrenia Pathogenesis and Clinical Findings […] dopaminergic transmission in mesocortical projection? […] dopaminergic transmission in mesolimbic projection […] Genetics (50% monozygotic twin risk, 6-13% 1st degree relative risk) […] Dopaminergic neurons here project into the limbic system, responsible for behaviors and emotions. […] Dopamine Hypothesis(predominant theory) […] Other biological theories (under investigation) […] Abnormalities of neurotransmitter (mainly dopamine) transmission in various regions of the brain […] Abnormal dopamine transmission here is thought to cause the Positive Symptoms of Schizophrenia […] Abnormal dopamine transmission here is thought to cause Negative Symptoms of Schizophrenia […] Notes: Although schizophrenia was largely thought to be caused by biological factors, we now recognize increasing roles of psychological factors (i.e. cognitive biases) and social factors (i.e. social stress or isolation) in its etiology.

• #7 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Multifaceted interactions between genetic and environmental risk factors give rise to schizophrenia. These risk factors also affect early brain development and shape the biological response to life experiences, thereby influencing the onset and progression of the disorder. […] Twin and family studies indicate that genetic factors can explain approximately 80% of the risk for schizophrenia. […] Genome-wide association studies have identified 130 genes predominantly associated with neural differentiation, organization, and transmission, which increase the risk of schizophrenia. […] Notably, nearly 30% of these genes are involved in the functioning of the presynaptic and postsynaptic elements of the glutamatergic synapse by impacting N-methyl-D-aspartic acid (NMDA) receptor transmission.

• #8 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  During neurodevelopment, redundant synapses are tagged by complement proteins such as C1q and other complement proteins including C3 and C4, in a process which triggers the phagocytosis of the synapse by microglia. […] The latest genome wide association study (GWAS) includes 76,755 schizophrenia patients and 243,649 controls, and identified 287 common variant loci associated with schizophrenia. […] These associations implicate genes involved in synaptic organisation, differentiation and transmission, and post-synaptic terms, with additional enrichment of genes playing roles in synaptic transmission and signalling. […] Early environmental insults, such as maternal infection, are risk factors for schizophrenia, and animal models of antenatal infection or immune challenge show that these affect synaptic development, with some effects enduring into adulthood.

• #9 Neurobiology of Schizophrenia: A Comprehensive Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9080788/

  Schizophrenia is a debilitating disease that presents with both positive and negative symptoms affecting cognition and emotions. […] There is evidence of significant genetic etiology involving multiple genes such as dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1). […] However, studies have shown that subcortical dopamine dysfunction is the key mechanism. […] The pathophysiology of schizophrenia is complex, and it has been studied for years with many factors yet to be discovered. Genetic studies show that schizophrenia involves different genetic loci and is highly pleiotropic. […] Among all neurotransmitters involved in the pathophysiology of schizophrenia, dopamine plays a major role in psychosis. […] The primary positive, negative, and cognitive symptoms of schizophrenia have been associated with many neurotransmitters, but the subcortical dopamine dysfunction remains to be the key factor in psychotic symptoms.

• #10 Schizophrenia pathophysiology: are we any closer to a complete model? | Annals of General Psychiatry | Full Text

  https://annals-general-psychiatry.biomedcentral.com/articles/10.1186/1744-859X-8-12

  Based on this, Mitteraue postulated the oligodendrocytic computation capacity theory, which ascertains that decomposition of the oligodendrocyte-axonic system may be responsible for symptoms leading to complete incoherence as seen in schizophrenia. […] Recent studies of twins and adoption studies support that schizophrenia is, at least partially, a genetic disorder. […] The current view is that the total susceptibility effect arises from a collection of small individual effects. […] Several major processes have been identified and are implicated as schizophrenia risk genes. […] The current view is that most of these genes can exert small individual effects and can aggregate by chance, associative mating or other mechanisms constituting increased risk for schizophrenia. […] In 2002, Straub et al. isolated a suspected schizophrenia susceptibility gene named DTNBP1.

• #11 Advances in the understanding of the pathophysiology of schizophrenia and bipolar disorder through induced pluripotent stem cell models | JPN

  https://www.jpn.ca/content/49/2/E109

  Overall the different SNPs or copy number variations associated with schizophrenia and bipolar disorder have been found to affect the expression of genes regulating glutamate neurotransmission, sodium and calcium signalling, cytoskeletal components, or cortical neurogenesis. […] Despite the important advancements deriving from studies involving animal models, genetic sequencing, neuroimaging, and postmortem observations, deciphering the pathophysiology of these disorders represents still a challenge. […] Recent progress in the field of stem cell research offers a promising avenue for understanding the neurodevelopmental and molecular alterations involved in these disorders and, potentially, for developing new treatment options. […] Overall, studies employing iPSCs in schizophrenia and bipolar disorder have adopted 2 main approaches. The first focuses on the genetic risk variants associated with these disorders and how the presence of these allelic variations in iPSC models affect molecular and cellular characteristics. The second focuses on the differences in neurodevelopmental processes, morphological characteristics, and neurotransmission recorded in iPSC-derived cells of patients and healthy donors.

• #12 Schizophrenia pathophysiology: are we any closer to a complete model? | Annals of General Psychiatry | Full Text

  https://annals-general-psychiatry.biomedcentral.com/articles/10.1186/1744-859X-8-12

  Epidemiologic studies, as well as studies from discordant identical twins, indicate that there are significant environmental risks for schizophrenia which exert pronounced effects on early brain development. […] It has been suggested that environmental factors combined with a genetic predisposition result in the manifestation of schizophrenia. […] Schizophrenia is marked by severe cognitive dysfunction or impairment. […] Currently, investigators are using functional imaging techniques to help improve the understanding of schizophrenia. […] Wolf et al. suggested that the working memory deficit is at the core of the cognitive impairment in schizophrenia, and that this lead to the higher deficits observed in schizophrenia patients. […] White matter abnormalities in the brain have also been correlated with schizophrenia.

• #13 5 Powerful Insights Into The Pathogenesis Of Schizophrenia – Delhi Mind Clinic

  https://www.delhimindclinic.com/pathogenesis-of-schizophrenia/

  Genetic predisposition plays a pivotal role in the pathogenesis of schizophrenia. Research shows that individuals with a family history of schizophrenia have a significantly higher risk of developing the condition. Twin and adoption studies estimate that genetic factors account for up to 80% of the risk. […] Schizophrenia is often described as a neurodevelopmental disorder. Abnormalities during brain development, particularly in the prenatal and early postnatal stages, are critical to understanding the pathogenesis of schizophrenia. […] The dopamine hypothesis remains one of the most widely studied theories in schizophrenia research. According to this hypothesis, dysregulation of dopamine pathways in the brain contributes significantly to the symptoms of schizophrenia. […] Environmental factors can significantly influence the pathogenesis of schizophrenia, particularly when combined with genetic vulnerability. […] Emerging evidence suggests that immune system dysfunction may play a role in the pathogenesis of schizophrenia. […] The pathogenesis of schizophrenia is a multifaceted process influenced by genetic, neurodevelopmental, environmental, and immunological factors.

• #14 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Schizophrenia, a serious mental illness, affects 1% of the global population and is marked by hallucinations, delusions, disorganized speech, grossly disorganized behavior, and negative signs and symptoms such as reduced emotional expression, avolition, and cognitive impairment. […] Causes include genetic, environmental, and neurobiological factors. No single gene is responsible; there is an interplay of multiple genetic factors. Environmental influences include prenatal and obstetrical risks, psychosocial stressors, and cannabis use. Neurobiologically, schizophrenia is associated with neurotransmitter dysfunction in dopamine and glutamate systems, as well as brain structural changes. […] The disorder’s etiology and pathophysiological mechanisms remain elusive due to its complexity and heterogeneity.

• #15 Schizophrenia pathophysiology: are we any closer to a complete model? | Annals of General Psychiatry | Full Text

  https://annals-general-psychiatry.biomedcentral.com/articles/10.1186/1744-859X-8-12

  Schizophrenia, a severe brain disorder that involves hallucinations, disordered thinking and deficiencies in cognition, has been studied for decades in order to determine the early events that lead to this neurological disorder. […] In addition, current data suggests neurodevelopmental or environmental causes such as viral infections and prenatal/perinatal complications. […] A number of models have been proposed to explain the mechanism for the development of schizophrenia in terms of the nature, timing and the course of brain changes; processes which are still not well understood. […] In order to improve treatment options and prognostic outcomes for schizophrenia it is necessary to understand the pathophysiology that contributes to this disease state. […] Based on early studies, it was believed that the structural brain changes that occur in schizophrenia were caused by early prenatal or perinatal insults, which can present a predisposition to the development of schizophrenia.

• #16 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Patients with schizophrenia exhibit both structural and functional brain abnormalities. Lateral ventricle enlargement by about 25%, coupled with an approximate 2% reduction in overall brain volume, primarily in the grey matter, is seen in schizophrenia. […] Several neurotransmitter systems have been implicated in the development of schizophrenia, with the dopaminergic and glutamatergic systems the leading contenders. […] The neurodevelopmental hypothesis of schizophrenia proposes that a mix of genetic risks and environmental factors during early brain development leads to the disorder. These influences, particularly significant in the prenatal and early life stages, set the stage for the emergence of symptoms of schizophrenia in early adulthood. […] Multiple molecular and neural circuit changes are linked to schizophrenia’s pathophysiology, but whether these changes are direct causes or adaptive responses to upstream dysfunctions is unclear.

• #17 Schizophrenia pathophysiology: are we any closer to a complete model? | Annals of General Psychiatry | Full Text

  https://annals-general-psychiatry.biomedcentral.com/articles/10.1186/1744-859X-8-12

  Weinberger’s findings suggest that schizophrenia occurs from non-specific histopathology that exists in the limbic system, diencephalon, and prefrontal cortex of the brain. […] Similar to Weinberger’s theory on susceptibility to schizophrenia, Benes et al. examined the anterior cingulate cortex (ACC) of postmortem schizophrenic brains. […] This study suggested that the development of schizophrenia was related to congenital abnormalities involving reduced number and altered interconnectivity of neurons in the ACC. […] More recently, Pantellis et al. have provided evidence to support the neurodevelopmental hypothesis for schizophrenia. […] Their studies suggested that schizophrenia is a disease resulting from limited progressive brain changes that occur during prenatal development and in stages prior to the onset of psychosis.

• #18 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. […] Based on this evidence, we propose version III of the synaptic hypothesis. […] This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. […] We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. […] The mechanisms governing synaptic elimination include microglia, which play a central role in synaptic elimination during normal brain maturation.

• #19 Causes of schizophrenia – Wikipedia

  https://en.wikipedia.org/wiki/Causes_of_schizophrenia

  The causes of schizophrenia that underlie the development of schizophrenia, a psychiatric disorder, are complex and not clearly understood. A number of hypotheses including the dopamine hypothesis, and the glutamate hypothesis have been put forward in an attempt to explain the link between altered brain function and the symptoms and development of schizophrenia. […] The exact pathophysiology of schizophrenia remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis. Other theories include the specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress. […] The first formulations of the dopamine hypothesis of schizophrenia came from post-mortem studies finding increased numbers of D2/D3 receptors in the striatum, and elevated cerebrospinal fluid levels of dopamine metabolites.

• #20 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Schizophrenia-Neural-Processes.aspx

  The neural processes involved in the pathophysiology of schizophrenia are not well understood, and there are several mechanisms that are thought to play a role. […] Several neural transmitters appear to be involved, particularly dopamine and glutamate. However, there are also other theories that consider dysfunction of interneurons, the immune system and oxidative stress. […] The dopamine hypothesis originated from the observation that many antipsychotic medications that helped to reduce the symptoms of schizophrenia, such as phenothiazines, had an antagonistic effect on the dopamine neurotransmitter. […] This led to the idea that dopamine plays a role in the pathophysiology of schizophrenia and was supported by further research showing that drugs with an agonist effect on dopamine, such as amphetamines, aggravate the psychotic symptoms associated with schizophrenia.

• #21 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Neurotransmitter abnormalities are central to the pathophysiology of schizophrenia, with dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) all playing roles. […] Excessive dopamine activity in the mesolimbic pathway, which runs from the ventral tegmental area to the limbic regions, is thought to contribute to the positive symptoms of schizophrenia. Reduced dopamine levels in the mesocortical pathway, connecting the ventral tegmental area to the cortex, may underlie negative symptoms and cognitive deficits. […] Understanding dopamine’s role in schizophrenia extends beyond the traditional dopamine hypothesis. There is a 2- to 4-week delay between antipsychotic medications’ peak blockade of D2 receptors and the clinical response. […] Moreover, the interplay between dopamine, glutamate, and GABA is critical in modulating the function of excitatory and inhibitory interneurons within cortical circuits.

• #22 Schizophrenia Pathogenesis and Clinical Findings | Calgary Guide

  https://calgaryguide.ucalgary.ca/schizophrenia-pathogenesis-and-symptoms/schizophrenia-pathogenesis-and-clinical-findings/

  Schizophrenia Pathogenesis and Clinical Findings […] dopaminergic transmission in mesocortical projection? […] dopaminergic transmission in mesolimbic projection […] Genetics (50% monozygotic twin risk, 6-13% 1st degree relative risk) […] Dopaminergic neurons here project into the limbic system, responsible for behaviors and emotions. […] Dopamine Hypothesis(predominant theory) […] Other biological theories (under investigation) […] Abnormalities of neurotransmitter (mainly dopamine) transmission in various regions of the brain […] Abnormal dopamine transmission here is thought to cause the Positive Symptoms of Schizophrenia […] Abnormal dopamine transmission here is thought to cause Negative Symptoms of Schizophrenia […] Notes: Although schizophrenia was largely thought to be caused by biological factors, we now recognize increasing roles of psychological factors (i.e. cognitive biases) and social factors (i.e. social stress or isolation) in its etiology.

• #23 Causes of schizophrenia – Wikipedia

  https://en.wikipedia.org/wiki/Causes_of_schizophrenia

  A meta-analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of dopamine transporters or dopamine D2/D3 receptors. […] Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. […] Beside the dopamine hypothesis, interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of schizophrenia. […] The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia.

• #24 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Neurotransmitter abnormalities are central to the pathophysiology of schizophrenia, with dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) all playing roles. […] Excessive dopamine activity in the mesolimbic pathway, which runs from the ventral tegmental area to the limbic regions, is thought to contribute to the positive symptoms of schizophrenia. Reduced dopamine levels in the mesocortical pathway, connecting the ventral tegmental area to the cortex, may underlie negative symptoms and cognitive deficits. […] Understanding dopamine’s role in schizophrenia extends beyond the traditional dopamine hypothesis. There is a 2- to 4-week delay between antipsychotic medications’ peak blockade of D2 receptors and the clinical response. […] Moreover, the interplay between dopamine, glutamate, and GABA is critical in modulating the function of excitatory and inhibitory interneurons within cortical circuits.

• #25 Causes of schizophrenia – Wikipedia

  https://en.wikipedia.org/wiki/Causes_of_schizophrenia

  A meta-analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of dopamine transporters or dopamine D2/D3 receptors. […] Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. […] Beside the dopamine hypothesis, interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of schizophrenia. […] The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia.

• #26 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Schizophrenia-Neural-Processes.aspx

  Dopamine is thought to be linked to the positive symptoms of schizophrenia and has a less profound effect on negative symptoms. […] However, in addition to dopamine, it is likely that another neurotransmitter, serotonin, is also involved in the pathophysiology. […] The neurotransmitter glutamate and the NMDA glutamate receptor are also thought to be involved in the neural processes of the brain that may lead to schizophrenia. […] In particular, low levels of glutamate receptors have been associated with patients who are affected by schizophrenia, suggesting a link between the two factors. […] To further this idea, medications that antagonize the glutamate receptor neural pathway, such as phencyclidine and ketamine, have been shown to mimic the cognitive symptoms of schizophrenia. […] However, it appears the glutamate has a more profound effect on the negative symptoms of schizophrenia, rather than the positive symptoms.

• #27 Neurobiology of Schizophrenia: A Comprehensive Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9080788/

  Presynaptic dopamine dysfunction appears to mediate psychosis in schizophrenia. […] Studies have shown that dopamine neurons not only release dopamine in a synaptic signal mode but also release co-transmitters glutamate and gamma-aminobutyric acid (GABA). […] Hypofunction of NMDA receptors may be associated with the pathogenesis of schizophrenia; therefore, treatment with D-serine, glycine, and sarcosine, which modulates NMDA receptors, can be beneficial, especially for negative symptoms. […] The extent to which these changes contribute to the pathophysiology of schizophrenia remains unclear. […] Schizophrenia is a disorder known for neuroanatomical changes over time. […] The widespread use of MRI has shown evidence of reduced gray matter volumes within the prefrontal, medial, and superior temporal lobes.

• #28 Schizophrenia: Mechanism of Action of Current and Novel Treatments

  https://www.psychiatrist.com/jcp/schizophrenia-mechanism-action-current-novel-treatments/

  Antipsychotics are effective for managing the positive symptoms of schizophrenia. […] Aiming at a novel treatment target, N-methyl-d-aspartate (NMDA) receptors, may also help to mediate the downstream release of dopamine as well as other neurotransmitters, such as glutamate and -aminobutyric acid (GABA), which are thought to be involved in the pathophysiology of schizophrenia. […] Dysfunctional NMDA receptor-mediated neurotransmission in the glutamate pathway may underlie the pathogenesis of schizophrenia. […] N-methyl-d-aspartate (NMDA) hypofunction affects several neurotransmitter systems, such as glutamate, -aminobutyric acid (GABA), and dopamine, and may provide a potential therapeutic target to address the positive, negative, and cognitive symptoms of schizophrenia. […] The glutamate hypothesis proposes that dysfunctional NMDA receptor-mediated neurotransmission in the glutamate pathway is at least one relevant aspect of the pathogenesis of schizophrenia. […] NMDA receptor hypofunction provides a potential explanation for the constellation of symptoms of schizophrenia, including positive, negative, and cognitive symptoms, as well as neuropsychological dysfunction.

• #29 Neurobiology of Schizophrenia: A Comprehensive Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9080788/

  Presynaptic dopamine dysfunction appears to mediate psychosis in schizophrenia. […] Studies have shown that dopamine neurons not only release dopamine in a synaptic signal mode but also release co-transmitters glutamate and gamma-aminobutyric acid (GABA). […] Hypofunction of NMDA receptors may be associated with the pathogenesis of schizophrenia; therefore, treatment with D-serine, glycine, and sarcosine, which modulates NMDA receptors, can be beneficial, especially for negative symptoms. […] The extent to which these changes contribute to the pathophysiology of schizophrenia remains unclear. […] Schizophrenia is a disorder known for neuroanatomical changes over time. […] The widespread use of MRI has shown evidence of reduced gray matter volumes within the prefrontal, medial, and superior temporal lobes.

• #30 Researchers Uncover Novel Mechanism behind Schizophrenia | School of Medicine | School of Medicine | Case Western Reserve University

  https://case.edu/medicine/about/newsroom/our-latest-news/researchers-uncover-novel-mechanism-behind-schizophrenia

  An international team of researchers led by a Case Western Reserve University School of Medicine scientist has uncovered a novel mechanism in which a protein neuregulin 3 controls how key neurotransmitters are released in the brain during schizophrenia. […] The new study helps explain why neuregulin 3 is central to the disease. […] We have identified a novel function of a schizophrenia susceptibility gene, neuregulin 3, which provides insight into cellular mechanisms of this devastating disorder and could lead to new therapeutic targets, said senior author Lin Mei, PhD. […] By understanding how neuregulin 3 acts in the brain, researchers could conceivably design drugs to restore its function during schizophrenia. […] Meis study outlines a previously unknown mechanism found in neurons affected by schizophrenia.

• #31 Researchers Uncover Novel Mechanism behind Schizophrenia | School of Medicine | School of Medicine | Case Western Reserve University

  https://case.edu/medicine/about/newsroom/our-latest-news/researchers-uncover-novel-mechanism-behind-schizophrenia

  The experiments not only supported a role for neuregulin 3 in schizophrenia, but also helped define types of neurons involved. […] They found it inhibits assembly of a complex of proteins at synapses, the place where adjacent nerve cells communicate. […] Neurons need the complex, called SNARE, to transmit certain neurotransmitters between each other. […] The researchers concluded that neuregulin 3 is critical to proper glutamate transmission in the brain. […] The findings suggest neuregulin 3 could serve as a new therapeutic target to help treat schizophrenia or other mental illnesses. […] Drugs that target neuregulin 3 could help restore glutamate levels in certain types of neurons—a novel approach to schizophrenia treatment. […] Identifying a novel mechanism of action is a prerequisite to understanding a disorder, and to development of therapeutic interventions, Mei said.

• #32 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Neurotransmitter abnormalities are central to the pathophysiology of schizophrenia, with dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) all playing roles. […] Excessive dopamine activity in the mesolimbic pathway, which runs from the ventral tegmental area to the limbic regions, is thought to contribute to the positive symptoms of schizophrenia. Reduced dopamine levels in the mesocortical pathway, connecting the ventral tegmental area to the cortex, may underlie negative symptoms and cognitive deficits. […] Understanding dopamine’s role in schizophrenia extends beyond the traditional dopamine hypothesis. There is a 2- to 4-week delay between antipsychotic medications’ peak blockade of D2 receptors and the clinical response. […] Moreover, the interplay between dopamine, glutamate, and GABA is critical in modulating the function of excitatory and inhibitory interneurons within cortical circuits.

• #33 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Schizophrenia-Neural-Processes.aspx

  Dopamine is thought to be linked to the positive symptoms of schizophrenia and has a less profound effect on negative symptoms. […] However, in addition to dopamine, it is likely that another neurotransmitter, serotonin, is also involved in the pathophysiology. […] The neurotransmitter glutamate and the NMDA glutamate receptor are also thought to be involved in the neural processes of the brain that may lead to schizophrenia. […] In particular, low levels of glutamate receptors have been associated with patients who are affected by schizophrenia, suggesting a link between the two factors. […] To further this idea, medications that antagonize the glutamate receptor neural pathway, such as phencyclidine and ketamine, have been shown to mimic the cognitive symptoms of schizophrenia. […] However, it appears the glutamate has a more profound effect on the negative symptoms of schizophrenia, rather than the positive symptoms.

• #34 Causes of schizophrenia – Wikipedia

  https://en.wikipedia.org/wiki/Causes_of_schizophrenia

  Another hypothesis is closely related to the glutamate hypothesis, and involves the dysfunction of inhibitory GABAergic interneurons in the brain. […] Another hypothesis states that abnormalities in myelination are a core pathophysiology of schizophrenia. […] Inflammation and immune system abnormalities are seen to be key mechanisms for the development of schizophrenia. […] Another theory that has gained support is that a large role is played in the disease by oxidative stress. […] The most consistent finding in post-mortem examinations of brain tissue is a lack of neurodegenerative lesions or gliosis. […] It has been hypothesized that in some people, development of schizophrenia is related to intestinal tract dysfunction such as seen with non-celiac gluten sensitivity or abnormalities in the gut microbiota. […] It has been suggested that sleep problems may be a core component of the pathophysiology of schizophrenia.

• #35 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Schizophrenia-Neural-Processes.aspx

  Kynurenic acid is an amino acid that may be involved in the neural pathways of schizophrenia, as it has been observed in higher concentration than normal in affected patients. […] This is thought to be due to the action of the acid as an NMDA receptor antagonist and resulting decrease in glutamate activity. […] Interneurons in the brain may also be involved in the pathways of schizophrenia, due to their GABAergic action. […] This emerging concept was originally suggested due to the observation that patients with schizophrenia were likely to have decreased levels of a particular protein in a small subset of cortical neurons. […] More recently, researchers have taken an interest in the role of oxidative stress in the neural pathways of schizophrenia. […] Unregulated reduction and oxidation reactions in early development may affect certain cells and lead to susceptibility to the disease.

• #36 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Schizophrenia-Neural-Processes.aspx

  Dopamine is thought to be linked to the positive symptoms of schizophrenia and has a less profound effect on negative symptoms. […] However, in addition to dopamine, it is likely that another neurotransmitter, serotonin, is also involved in the pathophysiology. […] The neurotransmitter glutamate and the NMDA glutamate receptor are also thought to be involved in the neural processes of the brain that may lead to schizophrenia. […] In particular, low levels of glutamate receptors have been associated with patients who are affected by schizophrenia, suggesting a link between the two factors. […] To further this idea, medications that antagonize the glutamate receptor neural pathway, such as phencyclidine and ketamine, have been shown to mimic the cognitive symptoms of schizophrenia. […] However, it appears the glutamate has a more profound effect on the negative symptoms of schizophrenia, rather than the positive symptoms.

• #37

  https://apcz.umk.pl/JEHS/article/view/JEHS.2020.10.08.039

  Schizophrenia is one of the most serious and frightening of all mental illnesses. It affects almost 1% of the population worldwide. The main concept and treatment of schizophrenia are based on the dopaminergic hypothesis. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid signaling. […] There are evidence that pathogenesis of schizophrenia include dysfunction in dopaminergic, serotoninergic, GABAergic, glutamatergic systems. The use of drugs that act on any of these systems reduces the symptoms of the disease. Nicotinic receptors may also be the target for drugs in treatment of schizophrenia. Studies about the role of nicotinic receptors in pathogenesis of schizophrenia show that it normalize many of the sensory processing deficits found in schizophrenia.

• #38 Much Ado About Something: Why There’s Excitement Behind Novel Mechanism of Action in Schizophrenia

  https://www.psychiatrictimes.com/view/much-ado-about-something-excitement-behind-novel-mechanism-action-schizophrenia

  Later this month, the US Food and Drug Administration is scheduled to share results of the New Drug Application for Bristol Myers Squibbs KarXT for the treatment of schizophrenia; the acceptance of the NDA was announced last year. As the date approaches, there is a growing sense of optimism for the drug and its novel mechanism of action, which could be the next breakthrough in the treatment of schizophrenia. […] Schizophrenia has a complicated pathophysiology affecting multiple receptor systems. Glutamate is one of the primary neurotransmitters in the brain and its signaling is modulated by other neurotransmitters. Patients with schizophrenia have shown dysfunction in dopamine, a neurotransmitter that modulates glutamate. However, the acetylcholine neurotransmitter system, which binds to muscarinic receptors (including M1 and M4), also plays a role in modulating glutamate, dopamine, and other neurotransmitters. Postmortem studies have shown reduced levels of M1 receptors in the brain cortex of patients with schizophrenia and it has been hypothesized that activation of M1 receptors may improve cognitive dysfunction while activation of M4 receptors may improve psychotic symptoms. Importantly, xanomeline, the active ingredient in KarXT, activates both the M1 and M4 receptors and thus may represent a uniquely effective therapeutic.

• #39 FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia | FDA

  https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia

  Today, the U.S. Food and Drug Administration approved Cobenfy (xanomeline and trospium chloride) capsules for oral use for the treatment of schizophrenia in adults. It is the first antipsychotic drug approved to treat schizophrenia that targets cholinergic receptors as opposed to dopamine receptors, which has long been the standard of care. Schizophrenia is a leading cause of disability worldwide. It is a severe, chronic mental illness that is often damaging to a persons quality of life, said Tiffany Farchione, M.D., director of the Division of Psychiatry, Office of Neuroscience in the FDAs Center for Drug Evaluation and Research. This drug takes the first new approach to schizophrenia treatment in decades. This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed.

• #40 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Schizophrenia-Neural-Processes.aspx

  Kynurenic acid is an amino acid that may be involved in the neural pathways of schizophrenia, as it has been observed in higher concentration than normal in affected patients. […] This is thought to be due to the action of the acid as an NMDA receptor antagonist and resulting decrease in glutamate activity. […] Interneurons in the brain may also be involved in the pathways of schizophrenia, due to their GABAergic action. […] This emerging concept was originally suggested due to the observation that patients with schizophrenia were likely to have decreased levels of a particular protein in a small subset of cortical neurons. […] More recently, researchers have taken an interest in the role of oxidative stress in the neural pathways of schizophrenia. […] Unregulated reduction and oxidation reactions in early development may affect certain cells and lead to susceptibility to the disease.

• #41 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  The synaptic hypothesis of schizophrenia has been highly influential. […] Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. […] Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. […] Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. […] Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss.

• #42 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. […] Based on this evidence, we propose version III of the synaptic hypothesis. […] This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. […] We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. […] The mechanisms governing synaptic elimination include microglia, which play a central role in synaptic elimination during normal brain maturation.

• #43 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  The synaptic hypothesis of schizophrenia has been highly influential. […] Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. […] Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. […] Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. […] Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss.

• #44 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  During neurodevelopment, redundant synapses are tagged by complement proteins such as C1q and other complement proteins including C3 and C4, in a process which triggers the phagocytosis of the synapse by microglia. […] The latest genome wide association study (GWAS) includes 76,755 schizophrenia patients and 243,649 controls, and identified 287 common variant loci associated with schizophrenia. […] These associations implicate genes involved in synaptic organisation, differentiation and transmission, and post-synaptic terms, with additional enrichment of genes playing roles in synaptic transmission and signalling. […] Early environmental insults, such as maternal infection, are risk factors for schizophrenia, and animal models of antenatal infection or immune challenge show that these affect synaptic development, with some effects enduring into adulthood.

• #45 Synaptic Pruning in Schizophrenia: Manifestations and Antecedents – IJFMR

  https://www.ijfmr.com/research-paper.php?id=44004

  Schizophrenia (SCZ) is a complex neurodevelopmental disorder characterised by structural and functional abnormalities in the brain. The synaptic pruning (SP) hypothesis, originally proposed by Irvin Feinberg (1982), suggests that excessive SP during adolescence contributes to the pathogenesis of SCZ. […] However, in SCZ, SP is aberrant and manifests as widespread grey matter depletion, reduced dendritic spine density, and cognitive deficits. This paper explores the structural and functional consequences of abnormal SP in SCZ and its potential antecedents, such as complement component 4 (C4) overexpression, neuroinflammation, NMDA receptor dysfunction, genes, and environmental deprivation and insults. Understanding the interplay between SP and schizophrenia pathophysiology may provide crucial insights into its neurodevelopmental origins and novel treatment strategies, especially for children showing early signs of psychosis.

• #46 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  The synaptic hypothesis of schizophrenia has been highly influential. […] Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. […] Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. […] Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. […] Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss.

• #47 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  A significant technological advance since the earlier versions of the synaptic hypothesis has been the ability to use stem cells from patients to derive neuronal cultures. […] This enables neuronal development to be studied in brain tissue with the same genetic background as patients. […] The evidence from the post-mortem and PET studies discussed above provides direct evidence for lower synaptic levels, particularly in frontal regions, in schizophrenia, whilst the iPSC studies show lower synaptic marker levels, synaptic signalling deficits and elevated microglial-mediated synaptic pruning in neurons derived from patients relative to controls. […] This model could explain why schizophrenia is rare in childhood: during this period, the net production of synapses provides a buffer against overactive pruning and synaptic dysfunction.

• #48 Neurobiology of Schizophrenia: A Comprehensive Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9080788/

  Presynaptic dopamine dysfunction appears to mediate psychosis in schizophrenia. […] Studies have shown that dopamine neurons not only release dopamine in a synaptic signal mode but also release co-transmitters glutamate and gamma-aminobutyric acid (GABA). […] Hypofunction of NMDA receptors may be associated with the pathogenesis of schizophrenia; therefore, treatment with D-serine, glycine, and sarcosine, which modulates NMDA receptors, can be beneficial, especially for negative symptoms. […] The extent to which these changes contribute to the pathophysiology of schizophrenia remains unclear. […] Schizophrenia is a disorder known for neuroanatomical changes over time. […] The widespread use of MRI has shown evidence of reduced gray matter volumes within the prefrontal, medial, and superior temporal lobes.

• #49 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Schizophrenia-Mechanisms.aspx

  The underlying mechanisms of schizophrenia are not entirely understood in their complexity by medical researchers at this point in time. […] These mechanisms include the function of neurotransmitters in the brain, as well as specific structural and functional characteristics of the brain. […] This hypothesis came about due to the low number of glutamate receptors observed in the brain of people who had been diagnosed with schizophrenia. […] A meta-analysis concluded that the size of the brain and hippocampal volume was reduced, whereas the ventricles appeared enlarged in people following an initial psychotic episode. […] The functional abnormalities of the brain in the pathophysiology of schizophrenia have been observed with the use of positron emission tomography (PET) scans. […] Current research suggests that cerebral blood decreases in the left parahippocampal region of individuals with schizophrenia.

• #50 Schizophrenia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539864/

  Patients with schizophrenia exhibit both structural and functional brain abnormalities. Lateral ventricle enlargement by about 25%, coupled with an approximate 2% reduction in overall brain volume, primarily in the grey matter, is seen in schizophrenia. […] Several neurotransmitter systems have been implicated in the development of schizophrenia, with the dopaminergic and glutamatergic systems the leading contenders. […] The neurodevelopmental hypothesis of schizophrenia proposes that a mix of genetic risks and environmental factors during early brain development leads to the disorder. These influences, particularly significant in the prenatal and early life stages, set the stage for the emergence of symptoms of schizophrenia in early adulthood. […] Multiple molecular and neural circuit changes are linked to schizophrenia’s pathophysiology, but whether these changes are direct causes or adaptive responses to upstream dysfunctions is unclear.

• #51 Frontiers | Unraveling the pathophysiology of schizophrenia: insights from structural magnetic resonance imaging studies

  https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1188603/full

  Neural substrate of schizophrenia involves various brain regions, including the prefrontal cortex (PFC), temporal lobe, and limbic system. However, frontal lobe dysfunction is one of the most consistent findings in schizophrenia. Studies have demonstrated decreased activation and structural abnormalities in the PFC of individuals with schizophrenia, which is associated with cognitive impairment and negative symptoms. […] One area of investigation in schizophrenia research has been structural brain abnormalities, which have been found to be present in many patients with the disorder. Specifically, abnormalities have been found in brain regions that are involved in a range of cognitive and emotional functions, including attention, memory, language, and social cognition, which are frequently impaired in individuals with schizophrenia.

• #52 Frontiers | Unraveling the pathophysiology of schizophrenia: insights from structural magnetic resonance imaging studies

  https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1188603/full

  The present study aimed to investigate differences in brain volume between patients with schizophrenia and healthy controls using voxel-by-voxel analysis with family-wise error correction method. Our findings indicate significant reductions in gray matter volume in various regions of the brain, including the right inferior frontal gyrus, right middle frontal gyrus, right superior frontal gyrus, right subcallosal gyrus, left middle temporal gyrus, left postcentral gyrus, and left cingulate gyrus. Additionally, we found significant reductions in white matter volume in several brain regions, including the left parahippocampal gyrus, left superior temporal gyrus, right fusiform gyrus, left middle temporal gyrus, left inferior frontal gyrus, right inferior frontal gyrus, right sub-gyral, and right middle frontal gyrus. Moreover, our analysis revealed significant increases in cerebrospinal fluid volume in the left third ventricle and left lateral ventricle regions of schizophrenic patients compared to healthy controls.

• #53 Frontiers | Unraveling the pathophysiology of schizophrenia: insights from structural magnetic resonance imaging studies

  https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1188603/full

  The present study aimed to investigate differences in brain volume between patients with schizophrenia and healthy controls using voxel-by-voxel analysis with family-wise error correction method. Our findings indicate significant reductions in gray matter volume in various regions of the brain, including the right inferior frontal gyrus, right middle frontal gyrus, right superior frontal gyrus, right subcallosal gyrus, left middle temporal gyrus, left postcentral gyrus, and left cingulate gyrus. Additionally, we found significant reductions in white matter volume in several brain regions, including the left parahippocampal gyrus, left superior temporal gyrus, right fusiform gyrus, left middle temporal gyrus, left inferior frontal gyrus, right inferior frontal gyrus, right sub-gyral, and right middle frontal gyrus. Moreover, our analysis revealed significant increases in cerebrospinal fluid volume in the left third ventricle and left lateral ventricle regions of schizophrenic patients compared to healthy controls.

• #54 The synaptic hypothesis of schizophrenia version III: a master mechanism | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02043-w

  Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. […] Based on this evidence, we propose version III of the synaptic hypothesis. […] This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. […] We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. […] The mechanisms governing synaptic elimination include microglia, which play a central role in synaptic elimination during normal brain maturation.

• #55

  https://link.springer.com/article/10.1134/S1022795423100101

  Human predisposition to neurological diseases such as schizophrenia, Alzheimers, Parkinsons and other neuropathologies is associated with genetic and environmental factors. […] This review explores the role of complex histocompatibility genes in the pathogenesis of schizophrenia, evaluating changes in the immune repertoire of T- and B-cell receptors in neuroinflammation. […] A role of the immune system in the pathogenesis of schizophrenia. […] Cytokines dysregulation in schizophrenia: a systematic review of psychoneuroimmune relationship. […] Immune system abnormalities in schizophrenia: an integrative view and translational perspectives. […] Neuroinflammation in schizophrenia: the role of nuclear factor kappa B. […] Systems biological assessment of altered cytokine responses to bacteria and fungi reveals impaired immune functionality in schizophrenia.

• #56 5 Powerful Insights Into The Pathogenesis Of Schizophrenia – Delhi Mind Clinic

  https://www.delhimindclinic.com/pathogenesis-of-schizophrenia/

  Genetic predisposition plays a pivotal role in the pathogenesis of schizophrenia. Research shows that individuals with a family history of schizophrenia have a significantly higher risk of developing the condition. Twin and adoption studies estimate that genetic factors account for up to 80% of the risk. […] Schizophrenia is often described as a neurodevelopmental disorder. Abnormalities during brain development, particularly in the prenatal and early postnatal stages, are critical to understanding the pathogenesis of schizophrenia. […] The dopamine hypothesis remains one of the most widely studied theories in schizophrenia research. According to this hypothesis, dysregulation of dopamine pathways in the brain contributes significantly to the symptoms of schizophrenia. […] Environmental factors can significantly influence the pathogenesis of schizophrenia, particularly when combined with genetic vulnerability. […] Emerging evidence suggests that immune system dysfunction may play a role in the pathogenesis of schizophrenia. […] The pathogenesis of schizophrenia is a multifaceted process influenced by genetic, neurodevelopmental, environmental, and immunological factors.

• #57 The Role of Cytokines in the Pathogenesis of Schizophrenia

  https://www.mdpi.com/2077-0383/10/17/3849

  Schizophrenia is a chronic mental illness of unknown etiology. A growing and compelling body of evidence implicates immunologic dysfunction as the key element in its pathomechanism. Cytokines, whose altered levels have been increasingly reported in various patient populations, are the major mediators involved in the coordination of the immune system. The available literature reports both elevated levels of proinflammatory as well as reduced levels of anti-inflammatory cytokines, and their effects on clinical status and neuroimaging changes. There is evidence of at least a partial genetic basis for the association between cytokine alterations and schizophrenia. […] Recent research indicates that subclinical inflammation in the CNS and immune dysregulation may play a role in the etiopathogenesis of schizophrenia, which is supported by immunogenetic evidence and a higher incidence of autoimmune diseases in patients with schizophrenia relative to the general population. Neuroinflammation can lead to white matter pathology, dysconnectivity, and thus to the onset of schizophrenia symptoms.

• #58 The Role of Cytokines in the Pathogenesis of Schizophrenia

  https://www.mdpi.com/2077-0383/10/17/3849

  Early childhood trauma has been associated with elevated peripheral levels of IL-6 and a faster elevation in IL-6 and IL-1 levels with age in healthy adults, which, in the case of IL-6, also seems to have an impact on neurophysiology, but not IQ. […] Gut microbiome dysbiosis affects behavior as well as the functioning and maturation of microglia. Dysbiosis may also influence the activity of astrocytes with the participation of type I interferons and tryptophan metabolites. […] There is a growing body of evidence for a relationship between alterations in cytokine levels and the structure of gray and white matter of the brain in schizophrenia. Cytokines that can easily penetrate the blood–brain barrier induce reactions that can cause a cascading inflammatory response within the central nervous system, which leads to the activation of microglia and a reduction in the number of astrocytes, neurotoxicity, abnormal synaptic pruning or nerve cell apoptosis. […] The dysfunction of glial cells, which are the second component of nervous tissue besides neurons, is proposed as one of the key elements of the etiopathogenesis of schizophrenia, and at least some of the abnormalities affecting them may be mediated by cytokines.

• #59 The Role of Cytokines in the Pathogenesis of Schizophrenia

  https://www.mdpi.com/2077-0383/10/17/3849

  Numerous studies, including many meta-analyses, demonstrate alterations in blood cytokine levels in schizophrenia patients compared to healthy controls. Additionally, they tend to manifest the increased mRNA expression of cytokine genes in lymphocytes relative to HC. This may stem from epigenetic mechanisms underlying the relationship between schizophrenia and stress in early childhood. […] The aim of this narrative review is to present the most valuable evidence on cytokine dysregulation in schizophrenia, the links between cytokine levels and psychopathological presentation, as well as their alterations in response to antipsychotics. We will also investigate the possible underpinnings of changes in the cytokine system. […] The role of immunological dysfunction in the etiopathogenesis of schizophrenia is also demonstrated by its association with disorders of known autoimmunological underpinnings. Schizophrenia has been shown to be associated with major histocompatibility complex A gene (MHC-A) polymorphisms, and with rheumatoid arthritis through major histocompatibility complex class II (MHC-II) or DRB1 chain gene (HLA-DRB1).

• #60 Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis | BMJ Open

  https://bmjopen.bmj.com/content/13/3/e067944

  Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. […] The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. […] The neuroimmune hypothesis of schizophrenia proposes that mild peripheral immune activation gives rise to an inflammatory response in the brain and neurobiological changes associated with psychotic illness. […] Prospective cohort studies show that these indices of mild immune activation precede the onset of symptoms. […] Furthermore, genetic variants known to increase IL-6 concentrations are associated with genetic risk of schizophrenia.

• #61 Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis | BMJ Open

  https://bmjopen.bmj.com/content/13/3/e067944

  Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. […] The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. […] The neuroimmune hypothesis of schizophrenia proposes that mild peripheral immune activation gives rise to an inflammatory response in the brain and neurobiological changes associated with psychotic illness. […] Prospective cohort studies show that these indices of mild immune activation precede the onset of symptoms. […] Furthermore, genetic variants known to increase IL-6 concentrations are associated with genetic risk of schizophrenia.

• #62 Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis | BMJ Open

  https://bmjopen.bmj.com/content/13/3/e067944

  These Mendelian randomisation studies eliminate the possibility that raised IL-6 concentrations are a consequence of environmental exposures associated with schizophrenia, such as obesity and smoking and instead suggest that IL-6 has a causal role in psychosis. […] This causal evidence strongly implicates IL-6, only an intervention study in patients can test the causal hypothesis. […] The neuroimmune hypothesis generally assumes that microglia, the brains resident immune cells, are activated and pathogenic in schizophrenia. […] However, whether microglia are the direct target of IL-6 is unclear and it is not certain that IL-6 can cross the bloodbrain barrier and/or increase its permeability to circulating inflammatory cells, cytokines and chemokines. […] A novel proposal is that Treg hypofunction accounts for mild peripheral immune disinhibition and dysregulated astroglialmicroglial interaction, such that microglia are driven into a developmental, synapse-pruning phenotype while astroglia disrupt neurotransmitter function.

• #63 Identifying serum lipidomic signatures related to prognosis in first-episode schizophrenia | BMC Psychiatry | Full Text

  https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-025-06802-7

  Dysregulation of lipid metabolism, particularly in phospholipids, sphingolipids, and fatty acids, has been implicated in the pathophysiologic mechanisms of SCZ. […] Research indicates that lipid dysregulation may stem from abnormal catabolism of membrane phospholipids and inflammatory responses, which can be partially reversed by therapeutic intervention. […] These findings suggest that lipids may be a potential biomarker for predicting response to antipsychotic drug treatment in SCZ. […] Significant progress has been made in the research on lipid biomarkers for predicting treatment response in SCZ. […] Given these gaps in the current research, we hypothesized that lipid profiles could function as prospective biomarkers for predicting responses to antipsychotic therapy. […] In this study, we selected lipids by integrating the results from LASSO and RF regression, which is a common machine-learning approach for variable selection in high-dimensional data.

• #64 Thieme E-Journals – Fortschritte der Neurologie · Psychiatrie / Abstract

  https://doi.org/10.1055/s-2007-1001178

  Phospholipase A2 (PLA2) is a key enzyme in the metabolism of phospholipids. PLA2 is enriched in neuronal membranes and plays an essential role in the functioning of membrane structures in the brain. Because a disordered phospholipid metabolism has been postulated in schizophrenia we started in 1985 a series of exploratory studies in an attempt to clarify the role of PLA2 in schizophrenic disorders. Our results can presently be summed up as follows: […] Drug-free schizophrenics showed significantly higher PLA2 activity in serum and in plasma as compared with healthy controls as well as with nonschizophrenic psychiatric patients; the latter did not differ from the control group with regard to PLA2 activity. These findings suggest that increased PLA2 activity might be specific for schizophrenia.

• #65 Thieme E-Journals – Fortschritte der Neurologie · Psychiatrie / Abstract

  https://doi.org/10.1055/s-2007-1001178

  Increased PLA2 activity in schizophrenic patients was not caused by the entry of pancreatic enzyme into circulation. Our findings in serum rather suggest that the increment reflects increased intracellular enzyme activity. We speculate that our results might reflect an increment of the intraneuronal PLA2 activity in the brain. The activation of PLA2 in the brain was found to result in changes in neuronal function due to alterations in receptor sensitivity as well as in neurotransmitter metabolism. The possibility that such PLA2-induced mechanisms are involved in the pathology of schizophrenia should be investigated in further experiments.

• #66 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Schizophrenia-Neural-Processes.aspx

  Kynurenic acid is an amino acid that may be involved in the neural pathways of schizophrenia, as it has been observed in higher concentration than normal in affected patients. […] This is thought to be due to the action of the acid as an NMDA receptor antagonist and resulting decrease in glutamate activity. […] Interneurons in the brain may also be involved in the pathways of schizophrenia, due to their GABAergic action. […] This emerging concept was originally suggested due to the observation that patients with schizophrenia were likely to have decreased levels of a particular protein in a small subset of cortical neurons. […] More recently, researchers have taken an interest in the role of oxidative stress in the neural pathways of schizophrenia. […] Unregulated reduction and oxidation reactions in early development may affect certain cells and lead to susceptibility to the disease.

• #67 Causes of schizophrenia – Wikipedia

  https://en.wikipedia.org/wiki/Causes_of_schizophrenia

  Another hypothesis is closely related to the glutamate hypothesis, and involves the dysfunction of inhibitory GABAergic interneurons in the brain. […] Another hypothesis states that abnormalities in myelination are a core pathophysiology of schizophrenia. […] Inflammation and immune system abnormalities are seen to be key mechanisms for the development of schizophrenia. […] Another theory that has gained support is that a large role is played in the disease by oxidative stress. […] The most consistent finding in post-mortem examinations of brain tissue is a lack of neurodegenerative lesions or gliosis. […] It has been hypothesized that in some people, development of schizophrenia is related to intestinal tract dysfunction such as seen with non-celiac gluten sensitivity or abnormalities in the gut microbiota. […] It has been suggested that sleep problems may be a core component of the pathophysiology of schizophrenia.

• #68 Advances in the understanding of the pathophysiology of schizophrenia and bipolar disorder through induced pluripotent stem cell models | JPN

  https://www.jpn.ca/content/49/2/E109

  Genetic studies of schizophrenia and bipolar disorder have highlighted how the expression of different genes related to activity of voltage-gated cation channels can be linked to the development of these 2 psychiatric disorders. […] Aberrant calcium signalling seems to be one of the primary features of the pathophysiological mechanisms of bipolar disorder. […] In recent years, more studies have reported the presence of various defects in mitochondria in schizophrenia and bipolar disorder, such as alterations in calcium signalling and buffering, reduction in the production of adenosine triphosphate (ATP), and aberrations in mitochondrial size and density. […] The current review provides a comprehensive overview on how iPSC studies hold promise for advancing our understanding of the main neuropathological alterations linked to schizophrenia and bipolar disorder.

• #69 Sp1 Expression Is Disrupted in Schizophrenia; A Possible Mechanism for the Abnormal Expression of Mitochondrial Complex I Genes, NDUFV1 and NDUFV2 | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000817

  Sp1 Expression Is Disrupted in Schizophrenia; A Possible Mechanism for the Abnormal Expression of Mitochondrial Complex I Genes,NDUFV1andNDUFV2 […] The prevailing hypothesis regards schizophrenia as a polygenic disease, in which multiple genes combine with each other and with environmental stimuli to produce the variance of its clinical symptoms. […] We further hypothesize that an abnormality in a ubiquitous transcription factor that participates in the regulation of numerous genes, either as the main activator/repressor or in combination with additional transcription factors, all differentially subjected to environmental stimuli, can lead to the heterogeneity observed in schizophrenia. The transcription factor Specificity protein 1 (Sp1), is such a candidate. […] These findings suggest that abnormality in Sp1, which can be the main activator/repressor or act in combination with additional transcription factors and is subjected to environmental stimuli, can contribute to the polygenic and clinically heterogeneous nature of schizophrenia. […] Herein we show for the first time that in schizophrenia Sp1 mRNA levels are altered in three different brain areas and in the periphery in a region specific manner. […] These results suggest Sp1 as a pathological factor in schizophrenia, which may explain the multi-gene manifestation of this disorder. […] The results of the present study, demonstrating disrupted expression of Sp1 associated with parallel impairments in complex I subunits, for which Sp1 is probably a transcription factor, suggest a key role for Sp1 in the pathogenesis of schizophrenia.

• #70 Sp1 Expression Is Disrupted in Schizophrenia; A Possible Mechanism for the Abnormal Expression of Mitochondrial Complex I Genes, NDUFV1 and NDUFV2 | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000817

  Sp1 Expression Is Disrupted in Schizophrenia; A Possible Mechanism for the Abnormal Expression of Mitochondrial Complex I Genes,NDUFV1andNDUFV2 […] The prevailing hypothesis regards schizophrenia as a polygenic disease, in which multiple genes combine with each other and with environmental stimuli to produce the variance of its clinical symptoms. […] We further hypothesize that an abnormality in a ubiquitous transcription factor that participates in the regulation of numerous genes, either as the main activator/repressor or in combination with additional transcription factors, all differentially subjected to environmental stimuli, can lead to the heterogeneity observed in schizophrenia. The transcription factor Specificity protein 1 (Sp1), is such a candidate. […] These findings suggest that abnormality in Sp1, which can be the main activator/repressor or act in combination with additional transcription factors and is subjected to environmental stimuli, can contribute to the polygenic and clinically heterogeneous nature of schizophrenia. […] Herein we show for the first time that in schizophrenia Sp1 mRNA levels are altered in three different brain areas and in the periphery in a region specific manner. […] These results suggest Sp1 as a pathological factor in schizophrenia, which may explain the multi-gene manifestation of this disorder. […] The results of the present study, demonstrating disrupted expression of Sp1 associated with parallel impairments in complex I subunits, for which Sp1 is probably a transcription factor, suggest a key role for Sp1 in the pathogenesis of schizophrenia.

• #71 Much Ado About Something: Why There’s Excitement Behind Novel Mechanism of Action in Schizophrenia

  https://www.psychiatrictimes.com/view/much-ado-about-something-excitement-behind-novel-mechanism-action-schizophrenia

  KarXT represents the first new mechanism for schizophrenia in over 50 years. We hope an approval of this first-generation muscarinic modulator KarXT will open the door to further innovation and other follow-on breakthroughs. […] Currently, no singular therapy is able to fully cure schizophrenia, but each new innovation and new drug mechanism brings us closer to that goal.

• #72 Schizophrenia: Mechanism of Action of Current and Novel Treatments

  https://www.psychiatrist.com/jcp/schizophrenia-mechanism-action-current-novel-treatments/

  Antipsychotics are effective for managing the positive symptoms of schizophrenia. […] Aiming at a novel treatment target, N-methyl-d-aspartate (NMDA) receptors, may also help to mediate the downstream release of dopamine as well as other neurotransmitters, such as glutamate and -aminobutyric acid (GABA), which are thought to be involved in the pathophysiology of schizophrenia. […] Dysfunctional NMDA receptor-mediated neurotransmission in the glutamate pathway may underlie the pathogenesis of schizophrenia. […] N-methyl-d-aspartate (NMDA) hypofunction affects several neurotransmitter systems, such as glutamate, -aminobutyric acid (GABA), and dopamine, and may provide a potential therapeutic target to address the positive, negative, and cognitive symptoms of schizophrenia. […] The glutamate hypothesis proposes that dysfunctional NMDA receptor-mediated neurotransmission in the glutamate pathway is at least one relevant aspect of the pathogenesis of schizophrenia. […] NMDA receptor hypofunction provides a potential explanation for the constellation of symptoms of schizophrenia, including positive, negative, and cognitive symptoms, as well as neuropsychological dysfunction.

• #73

  https://www.healio.com/cme/psychiatry/20240709/exploring-the-mechanism-of-action-of-emerging-schizophrenia-treatments/overview

  Schizophrenia is a psychiatric continuum that is now viewed as a complex neurobiologic disease involving a variety of neural networks that go beyond the well-studied dopaminergic pathways. […] While excessive or dysregulated dopamine is still seen to be fundamental to the pathophysiology of this disease, recent research suggests the key to treating symptoms across all domains may lie in developing therapeutics that target different neurotransmitters. […] Identify the neural pathways and predominant neurotransmitters involved in the pathophysiology of schizophrenia symptom domains.

• #74 Neurotransmitter pathways involved in current and novel mechanism-action schizophrenia treatments – Neurotorium

  https://neurotorium.org/image/neurotransmitter-pathways-involved-in-current-and-novel-mechanism-action-schizophrenia-treatments/

  A. Dopaminergic pathways are involved in positive, negative, and cognitive symptoms of schizophrenia and are affected by currently available first- and second-generation antipsychotics that act as dopamine antagonists or partial agonists and target psychosis. […] C. Glutamatergic pathways are involved in positive, negative, and cognitive symptoms of schizophrenia and are affected by the M1/M4 receptor agonist xanomeline+tropsium targeting psychosis, and the glycine transporter-1 inhibitor, iclepertin, and the d-amino acid oxidase (DAOO) inhibitor luvadaxistat, each targeting cognition. […] D. Muscarinic M1 acetylcholine pathways are involved in positive and cognitive symptoms of schizophrenia and are affected by the M1/M4 receptor agonist xanomeline+tropsium targeting psychosis and cognition.

• #75 Much Ado About Something: Why There’s Excitement Behind Novel Mechanism of Action in Schizophrenia

  https://www.psychiatrictimes.com/view/much-ado-about-something-excitement-behind-novel-mechanism-action-schizophrenia

  Later this month, the US Food and Drug Administration is scheduled to share results of the New Drug Application for Bristol Myers Squibbs KarXT for the treatment of schizophrenia; the acceptance of the NDA was announced last year. As the date approaches, there is a growing sense of optimism for the drug and its novel mechanism of action, which could be the next breakthrough in the treatment of schizophrenia. […] Schizophrenia has a complicated pathophysiology affecting multiple receptor systems. Glutamate is one of the primary neurotransmitters in the brain and its signaling is modulated by other neurotransmitters. Patients with schizophrenia have shown dysfunction in dopamine, a neurotransmitter that modulates glutamate. However, the acetylcholine neurotransmitter system, which binds to muscarinic receptors (including M1 and M4), also plays a role in modulating glutamate, dopamine, and other neurotransmitters. Postmortem studies have shown reduced levels of M1 receptors in the brain cortex of patients with schizophrenia and it has been hypothesized that activation of M1 receptors may improve cognitive dysfunction while activation of M4 receptors may improve psychotic symptoms. Importantly, xanomeline, the active ingredient in KarXT, activates both the M1 and M4 receptors and thus may represent a uniquely effective therapeutic.

• #76 Neurotransmitter pathways involved in current and novel mechanism-action schizophrenia treatments – Neurotorium

  https://neurotorium.org/image/neurotransmitter-pathways-involved-in-current-and-novel-mechanism-action-schizophrenia-treatments/

  E. Muscarinic M4 acetylcholine pathways are involved in positive symptoms of schizophrenia and are affected by the M1/M4 receptor agonist xanomeline+tropsium and by the M4 positive allosteric modulator (PAM) emraclidine, each targeting psychosis. […] F. The trace amine-associated receptor 1 (TAAR-1) system is mainly located intracellularly and interacts with trace amines, also called false neurotransmitters, as they are not released from presynaptic terminals to stimulate postsynaptic receptors; instead when stimulated by trace amines or pharmacologic agonists, TAAR-1 receptors form heterodimer complexes with presynaptic and postsynaptic dopamine receptors, enhancing presynaptic dopamine autoreceptor activity, thereby reducing presynaptic dopamine synthesis, and reducing postsynaptic dopamine receptor availability and affinity for dopamine, reducing psychosis.

• #77 Researchers uncover novel mechanism behind schizophrenia

  https://medicalxpress.com/news/2018-02-uncover-mechanism-schizophrenia.html

  By studying brain samples from the mice, the researchers learned how neuregulin 3 works at the cellular level. They found it inhibits assembly of a complex of proteins at synapses, the place where adjacent nerve cells communicate. Neurons need the complex, called SNARE, to transmit certain neurotransmitters between each other. In particular, SNARE complex helps neurons transmit glutamate—the most common „excitatory” neurotransmitter in the brain. Glutamate helps activate neurons and is essential for learning. Glutamate imbalances can cause schizophrenic symptoms. […] The researchers concluded that neuregulin 3 is critical to proper glutamate transmission in the brain. The findings suggest neuregulin 3 could serve as a new therapeutic target to help treat schizophrenia or other mental illnesses. Drugs that target neuregulin 3 could help restore glutamate levels in certain types of neurons—a novel approach to schizophrenia treatment.

• #78 Identifying serum lipidomic signatures related to prognosis in first-episode schizophrenia | BMC Psychiatry | Full Text

  https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-025-06802-7

  Dysregulation of lipid metabolism, particularly in phospholipids, sphingolipids, and fatty acids, has been implicated in the pathophysiologic mechanisms of SCZ. […] Research indicates that lipid dysregulation may stem from abnormal catabolism of membrane phospholipids and inflammatory responses, which can be partially reversed by therapeutic intervention. […] These findings suggest that lipids may be a potential biomarker for predicting response to antipsychotic drug treatment in SCZ. […] Significant progress has been made in the research on lipid biomarkers for predicting treatment response in SCZ. […] Given these gaps in the current research, we hypothesized that lipid profiles could function as prospective biomarkers for predicting responses to antipsychotic therapy. […] In this study, we selected lipids by integrating the results from LASSO and RF regression, which is a common machine-learning approach for variable selection in high-dimensional data.

• #79 Identifying serum lipidomic signatures related to prognosis in first-episode schizophrenia | BMC Psychiatry | Full Text

  https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-025-06802-7

  To obtain the optimal lipid biomarker, we identified a set of three potential lipid biomarkers based on logistic regression to distinguish responders from non-responders with high accuracy. […] These findings collectively highlight the potential role of PE in the SCZ treatment from different perspectives. […] These findings suggest that the therapeutic effects of antipsychotics may involve the regulation of lipid homeostasis, especially the restoration of PE function. […] Although the precise mechanism by which increased TG levels improve drug response is not fully understood, research suggests that serum lipids may influence treatment outcomes by changing the pharmacokinetics of antipsychotic drugs. […] In summary, our study identified three potential candidate lipid biomarkers through a comprehensive analysis of lipidomics.

• #80 Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis | BMJ Open

  https://bmjopen.bmj.com/content/13/3/e067944

  Crucially, we will measure IL-6 in addition to cellular and molecular markers of immune function and investigate how they correlate with central markers and clinical state. […] These trials have generally tested broad spectrum agents, such as non-steroidal anti-inflammatory drugs, with no attempt to stratify patients according to evidence of inflammation. […] A trial using tocilizumab, a humanised monoclonal antibody (mAb) against the IL-6 receptor, currently licensed in the UK for treatment of rheumatoid arthritis (RA) and severe COVID-19, reported no improvements in any clinical measure in a small sample of 36 patients with established schizophrenia. […] However, as mentioned previously, no stratification by inflammatory markers or any mechanistic immune measures was applied. […] A randomised controlled trial of infliximab, an antitumour necrosis factor alpha mAb, reported that antidepressant response was associated with higher CRP levels at baseline, suggesting that patients with evidence of immune activation may be better candidates for immunotherapy trials.

• #81 Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis | BMJ Open

  https://bmjopen.bmj.com/content/13/3/e067944

  The primary aim of this trial is to examine potential mechanisms by which IL-6 affects anhedonia, psychotic symptoms and cognition. […] This will provide further evidence for a potential causal role of inflammation in psychosis. […] Our secondary hypothesis is that reduction in peripheral inflammation after tocilizumab infusion in patients with psychosis and evidence of inflammation will be associated with central measures of oxidative stress and relevant resting state brain function.

• #82 5 Powerful Insights Into The Pathogenesis Of Schizophrenia – Delhi Mind Clinic

  https://www.delhimindclinic.com/pathogenesis-of-schizophrenia/

  Genetic predisposition plays a pivotal role in the pathogenesis of schizophrenia. Research shows that individuals with a family history of schizophrenia have a significantly higher risk of developing the condition. Twin and adoption studies estimate that genetic factors account for up to 80% of the risk. […] Schizophrenia is often described as a neurodevelopmental disorder. Abnormalities during brain development, particularly in the prenatal and early postnatal stages, are critical to understanding the pathogenesis of schizophrenia. […] The dopamine hypothesis remains one of the most widely studied theories in schizophrenia research. According to this hypothesis, dysregulation of dopamine pathways in the brain contributes significantly to the symptoms of schizophrenia. […] Environmental factors can significantly influence the pathogenesis of schizophrenia, particularly when combined with genetic vulnerability. […] Emerging evidence suggests that immune system dysfunction may play a role in the pathogenesis of schizophrenia. […] The pathogenesis of schizophrenia is a multifaceted process influenced by genetic, neurodevelopmental, environmental, and immunological factors.

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