Knowledge Translation

Study	Journal	Year Published	Discussion / Conclusion / Results	Significance of Results	Recommendations for Future Studies
Recent Advances in the Genetics of Schizophrenia	Molecular Neuropsychiatry	2018	The progress in the genetics of schizophrenia in the last decade has been remarkable. We used to have not a single known genetic risk variant or gene, and failure to replicate prior reports was the norm. That was a difficult period for psychiatric genetics investigators that still has consequences to the way some view our field. Today, we know of numerous robustly supported genetic variants, perhaps more than we hoped for, as well as CNVs, and we have strong evidence for the involvement of rare and de novo variants with stronger effects on the risk. To allow this progress, large consortia have undertaken the recruitment of cohorts of several thousands of subjects, whose genetic analysis has been made possible by technological advancements. As this important work continues, it is now time to make sense out of these hundreds of risk factors and see how they can aid the fight against disease. Creating animal models for schizophrenia based on the results of GWAS is challenging. The diagnosis in humans is made by interview, which requires verbal interaction, and there is no objectively measurable phenotype such as a laboratory test. The GWAS variants are mostly non-coding, which limits our ability to accurately recapitulate them in other animals. In addition, even if the effect of the GWAS variants could be accurately mimicked, their resulting increase in risk is so small that such a mutant animal would be unlikely to show a phenotype. On the other hand, rare variants of larger effect have a level of uncertainty, as most studies report enrichments across many genes rather than definite involvement of individual variants. Studies in mice have employed knockout or knock-in strategies for a variety of genes with varying degrees of supporting evidence, and have examined schizophrenia-related behavioral domains and phenotypes similar to the endophenotypes described above. Discussing them is beyond the scope of this review, but there are many other excellent reviews of mouse models, the insights they have provided, and the associated challenges.	More recently, new approaches to disease models are beginning to show significant promise for schizophrenia research. The ability to manipulate human cells to induce pluripotency and differentiation and the achievement of accurate and efficient genome editing are advancements that may provide a powerful means to study the biology underlying the risk. The major advantage is that they allow us to work on a human genomic background and even to create human pluripotent cells that differ only at specific risk variants. These can be differentiated into the cell type of choice for phenotyping, or even used to generate and study brain organoids. The applications one can imagine are only limited by what is ethical to do in a lab. The small effect sizes may still be a problem, but others and we have shown that when one works with modified or edited cells, small effect variants can lead to robust cellular phenotypes. These technologies are new, and there is still much space for improvement, including editing efficiency, uniform and specific differentiation, the time needed for maturation, and the faithful recapitulation of cortical circuits by organoids Nevertheless, the genetic findings are there and the tools for us to understand them are rapidly evolving, giving hope for significant breakthroughs within the next decade. Despite the successes and promise for the future, obstacles in the biological interpretation of GWAS signals in schizophrenia remain. It is significant to know of the genes and variants leading to risk, but given the low odds ratios, it is difficult to measure and resolve their downstream consequences that can lead to disease. W hile there is no longer doubt these variants, either themselves of those genotypically correlated to them, increase the risk, they are certainly not deterministic and cannot be referred to as causal. Nevertheless the number of such variants is large and increasing. Cellular models and genome editing may reveal aspects of their weak effects on neuronal homeostasis, and similarities between them might lead to the perturbed gene networks. Such discoveries are likely not far down the road and could provide direct targets for intervention.	The agnostic nature of this type of genetics research does not lend itself to evident narratives on the etiology of the disease, which is reflected in this review. At the same time though, it does not rely on existing knowledge allowing surprising discoveries and breakthroughs. It might be too early to make up the entire story from the current discoveries but, as opposed to just a decade ago, we are certainly on the way there.
The Genetics of Schizophrenia	Research in Translation	2017	There are good suggestions that these studies have identifi ed plausible candidate genes for schizophrenia. The evidence for several genes involved including DISC1, DTNBP1, NRG1, and RGS4. Each of these genes has received support from multiple lines of evidence with imperfect consistency: The case for each of these as a candidate gene for schizophrenia is supported by linkage studies The preponderance of association study findings provides further support mRNA from each gene is expressed in the prefrontal cortex as well as in other areas of the brain and Additional neurobiological data link the functions of these genes to biological processes thought to be related to schizophrenia (e.g. DISC1 modulates neurite outgrowth) There is an extensive literature on the involvement of NRG1 in the development of the CNS, RGS4 may modulate intracellular signaling for many G-protein-coupled receptors. DTNBP1 and RGS4 have been reported to be differentially expressed in postmortem brain samples of individuals with schizophrenia.	This encouraging summation of work in progress masks the lack or consistent replication for the same markers and haplotypes across studies. The literature supports the contention that genetic variation in these genes is associated with schizophrenia, but it lacks impressive consistency in the precise genetic regions and alleles implicated. In contrast, association studies of other complex human genetic diseases have produced unambiguous, consistent, and clear-cut hard replication.	Schizophrenia is hypercomplex and we need to invoke more complicated genetic models than other biomedical disorders.
The Role of Genetics in the Etiology of Schizophrenia			Developments in treatment still lag compared to discoveries of new genetic associations for complex disorders but this situation is expected to change as biological research makes inroads into still purely statistical associations. There is a strong temptation to accept the simplest observations as the most meaningful and the only ones that merit follow-up. Research in model organisms shows that most phenotypes are the result of complicated genetic architectures: multiple genes, often showing pleotropy, epistasis and even single mutation effects differing with genetic background and environment This landscape will probably be true for complex human behavioral traits as well	Explanations relying on single genes are unlikely to capture the fundamental complexity of most human complex traits, and all the associated genetic variation needs to be pursued to understand the pathophysiology of a complex disorder. A task of utmost importance is the integration of the spectrum of mutations found in schizophrenia into a system that takes into account constantly changing environments and evolution.	It is anticipated that as genetic discoveries accumulate, the application of a myriad of tools from systems biology (e.g., genomics, transcriptomics, proteomics, etc.) will lead to a delineation of biological pathways involved in the pathophysiology of schizophrenia, and eventually to new therapies
Gene Expression Over the Course of Schizophrenia: From Clinical High-Risk For Psychosis to Chronic Stages	npj Schizophrenia volume 5, Article number: 5	2019	MBP and NDEL1 were upregulated in FEP compared to all other groups DGCR8 was downregulated in FEP compared to HC and CHR DGCR2 was downregulated in CSZ compared to FEP and HCs DISC1 was upregulated in schizophrenia compared to controls or FEP, possibly induced by the rs3738398 and rs10864693 genotypes, which were associated with DISC1 expression and UFD1 was upregulated in CSZ and CHR compared to FEP and HC.	The results indicate changes in gene expression profiles throughout the different clinical stages of Shizophrenia, reinforcing the need for staging approaches to better capture Schizophrenia heterogeneity. Their findings could be useful for creating a biological signature that is able to predict a psychotic event or help to find adequate treatment and decrease the illness time without a treatment. In this sense, a better characterization of each stage of schizophrenia is essential to improve the understanding of the pathogenesis of the disorder.	There is a need for more predictive markers and an understanding of the biological mechanisms underlying the onset of psychosis. A better understanding of the biological changes in the different stages of schizophrenia is essential to allow for the identification of these markers,
Signs of asphyxia at birth and risk of schizophrenia. Population-based case-control study	Br J Psychiatry. Nov;179:403-8	2001	There was a strong association between signs of asphyxia at birth and schizophrenia (OR 4.4; 95% C11.9-10.3) after adjustment for other obstetric complications, maternal history of psychotic illness and social class.	Signs of asphyxia at birth are associated with an increased risk of schizophrenia in adults. The results support a relationship between hypoxia at birth and schizophrenia, but some of the indicators of foetal disturbance (e.g. pre-eclampsia and prematurity) could not be dismissed as risk factors for schizophrenia. Disorders (such as pre-eclampsia) could reduce the supply of nutrients, including glucose adn oxygen which would interfere with brain development. In contrast, an infant who has developed normally may experience relatively short-term insults around the time of birth because of hypoxia Hypoxic brain damage is particularly seen in the brain-stem nuclei, hippocampus and cortex and is throught to be caused by acidosis and waste products, including amino acids and free radicals NMDA receptors are considered to play a key role Reduced volume of hippocampus has recently been described in schizophrenia patients with a history of obstetric complications.	Greater understanding of the effect of hypoxia on brain development adn adult brain function will probably help us to understand more about the pathogenesis of schizophrenia.
Obstetric Complications and Schizophrenia: Historical and Meta-Analytic Review	Am J Psychiatry	2002	The meta-analytic synthesis of the prospective population-based studies revealed that three groups of complications were significantly associated with schizophrenia: Complications of pregnancy (bleeding, diabetes, rhesus incompatibility, preeclampsia) Abnormal fetal growth and development: (low birthweight, congenital malformations, reduced head circumference) and Complications of delivery (uterine atony, asphyxia, emergency Cesarean section). Current methods for studying the relationship between obstetric complications and schizophrenia merely allow us to report associations and, as a result, we have become stuck at the point of reporting risk factors of “vanishingly small effect” over and over again. Innovative approaches include the use of animal models to study effects of prenatal infection and the analysis of large cohorts with detailed prenatal data and stored prenatal serum. As we enter what some researchers have called a new age of epidemiology for schizophrenia, the combination of larger cohorts, new paradigms, and modern statistical and molecular techniques provides the opportunity to discover how obstetric complications contribute to the causation of schizophrenia.	Current methods of investigating the relationship between obstetric complications and schizophrenia are reaching the limit of their usefulness. Lack of statistical power to measure small and interactive effects and lack of detailed information about the prenatal period are major problems with current approaches. A combination of disciplines and approaches will be needed to elucidate the mechanisms underlying these small but important associations.	Research in this area will need to move beyond the domain of epidemiology and involve other disciplines (such as developmental biology, neuropathology, and genetics)
Neurobiology of Schizophrenia	Neuron Volume 52, Issue 1, 5 October	2006	The molecular genetics of schizophrenia are sufficiently advanced such that etiology-based studies of the neurobiology of schizophrenia are both justified and feasible. The field is still in its infancy, and we must struggle to integrate our rudimentary knowledge of schizophrenia genetics with our scarcely better developed understanding of normal human brain function. Additional genetic studies are indispensable in this effort, and will now be facilitated by genome-wide methods for study of association and methods to systematically investigate variations in genomic copy number. Epigenetic modification, such as methylation, may also prove relevant Mouse models will make it possible to test pathogenic hypotheses. The mouse models generated to date have been based on the study of Mendelian disorders The more subtle etiologies of schizophrenia and other psychiatric disorders may make more complex genetic models important. For instance, it may be important to generate models with splicing alterations in neuregulin 1 or with amino acid polymorphisms in COMT or DISC1. In addition, it may be important to use inducible or other conditional systems in order to mimic the effect of activation of the genetic lesion in particular tissues at particular times. In addition to mouse models, genetic models in other organisms may be very useful. Unlike in neurodegenerative diseases, it may be difficult to use Drosophila or other invertebrates as models for the complexities of human psychiatric disorders. For understanding alterations of cortical development, zebrafish, in which development can be directly visualized, may prove suitable. Other species with more complex social behaviors and more complex cognition may ultimately be necessary. Perhaps genetically modified primates may become an important source of models, however, human patients must remain the gold standard.	Mouse models will make it possible to test pathogenic hypotheses. Studies of genetics and clinical and imaging phenotypes can increasingly be integrated. DISC1 appears to act as a scaffold for protein interactions, and some of these interacting proteins have altered expression in schizophrenia These interactors will be helpful for understanding pathogenesis, and can themselves serve as potential candidate genes to test for mutations. Thus, a neurogenetic approach based on candidate genes ) may now become possible. The DISC1 interacting protein Lis1 is related to lissencephaly, highlighting the idea that schizophrenia, as a subtle disorder of cerebral cortical development, is related to more severe disorders of cerebral cortical development. Study of the different genetic etiologies of schizophrenia will also improve understanding of the schizophrenia phenotype, and also understanding of affective disorder and potentially other related major psychiatric illnesses, just as study of the different genes causing lissencephaly has allowed a more careful classification of the phenotypes of lissencephaly Some of the genes, such as dysbindin, appear to be related more specifically to schizophrenia, perhaps especially deficit schizophrenia, while others such as DISC1 and neuregulin 1 can relate to both schizophrenia and affective disorder. The genes associated with schizophrenia may have a spectrum of different pathogenic effects, altering neuronal development, neuronal plasticity, and signal transduction. While undoubtedly a great oversimplification, it may be of heuristic value to postulate that variations in particular genes can affect particular neurobiological processes in turn causing specific phenotypes. For instance, effects on neurodevelopment may be more closely associated with schizophrenia, while effects on signal transduction may be more likely to cause affective disorder.	Future imaging studies may be able to combine fMRI with DTI to trace functionally identified circuits. DISC1 may offer unique opportunities for inroads into understanding the biology of schizophrenia. DISC1 may serve as a kind of Rosetta Stone for schizophrenia research, helping to connect disparate domains. Testing these broader hypotheses will require integration of research in: Biochemistry Cell biology Mouse genetics Neuroimaging and Human genotype-phenotype correlations. These studies may allow us to reconceptualize our definitions of the psychiatric disorders, including schizophrenia, based on a better understanding of etiology and pathogenesis.
Neurobiology of Schizophrenia Onset	Current Top Behaviour Neuroscience	Tsung-Ung W. Woo	Recent findings suggest that disturbances of a specific subset of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV), which may regulate the course of postnatal developmental experience-dependent synaptic plasticity in the cerebral cortex, including the prefrontal cortex (PFC), may be involved in the pathogenesis of the onset of this illness. Specifically, converging lines of evidence suggest that oxidative stress, extracellular matrix (ECM) deficit and impaired glutamatergic innervation may contribute to the functional impairment of PV neurons, which may then lead to aberrant developmental synaptic pruning of pyramidal cell circuits during adolescence in the PFC. In addition to promoting the functional integrity of PV neurons, maturation of ECM may also play an instrumental role in the termination of developmental PFC synaptic pruning; thus, ECM deficit can directly lead to excessive loss of synapses by prolonging the course of pruning. Together, these mechanisms may contribute to the onset of schizophrenia by compromising the integrity, stability, and fidelity of PFC connectional architecture that is necessary for reliable and predictable information processing.		Further characterization of neurobiological mechanisms will have implications for the conceptualization of rational strategies for the diagnosis, early intervention, and prevention of this debilitating disorder.
Neurobiology of schizophrenia: search for the elusive correlation with symptoms	Frontiers in Human Neuroscience	2012	Efforts to find robust correlations between specific symptoms and specific neurobiological measures in schizophrenia would likely achieve more success if such studies employed larger sample sizes where confidence intervals are tighter and spurious correlations are less likely. The field needs to make advances in the measurement of symptoms, going beyond the retrospective interview-based ratings of one or a few items that typify the approach taken in current studies. Examples of such approaches include multi-item ratings scales for hallucinations like the psychotic symptom rating scale, real-time event sampling to reduce the reliance on patient’s retrospective accounts of their symptoms, and assessments of symptoms at multiple time points over the illness course to facilitate the distinction between trait- and state-related variation in symptom severity. Finally, greater emphasis needs to be placed on accurate estimation of the reliability of symptom measurements, as well as the reliability of the neurobiological measures that are correlated with symptom severity. Studies of medication naïve first-episode patients is a potentially useful strategy for capturing variation in primary symptom severity with the confounding effects of medication, but such patients are difficult to recruit and the duration of time that medication can be ethically withheld is fairly limited. Moreover, to the extent that schizophrenia involves a progressive pathophysiology over the illness course, symptom correlations present at the onset of illness may not hold for chronic patients. That symptoms may depend on the stage of illness is supported by studies that suggest that positive symptoms become less severe and negative symptoms more prominent in the later stages of schizophrenia In addition, studying samples of schizophrenia patients who have transiently discontinued their medication or who choose not to take medication is another approach to capturing symptom variation in the absence of medication confounds. However, this approach may not yield symptom correlations that generalize to the entire population of schizophrenia patients, particularly to the extent that chronic patients who can live independently in the community without medication may not be representative of schizophrenia patients in general. One strategy that attempts to overcome the limitations of correlational brain-symptom data in clinical research studies is to use pharmacological challenges with agents that affect specific neuroreceptors in order to transiently exacerbate symptoms in patients, or to transiently induce schizophrenia-like symptoms in healthy volunteers. This strategy is exemplified by the use of the NMDA-receptor antagonist, ketamine, in challenge studies with patients and healthy volunteers, to test the hypothesis that NMDA-receptor hypofunction contributes to both clinical symptoms and neurocognitive deficits in schizophrenia. Another promising approach to overcoming the correlation–causation conundrum that is still in its early stages of development is the use of transcranial magnetic stimulation (TMS) to transiently perturb specific brain regions and circuits. While repetitive TMS has already been studied as a potential treatment for auditory hallucinations, the possibility of using TMS targeted at specific brain regions to transiently increase or decrease specific symptoms in order to provide evidence for the causal role of that brain region in producing or modulating the symptom remains largely unexplored. Nonetheless, both the pharmacological probe and the TMS probe approach to establishing causal connections between brain function and specific symptoms have some conceptual limitations. In particular, even if manipulating brain function with these methods can reproduce schizophrenia-like symptoms, this does not preclude the possibility that distinctly different pathophysiological mechanisms give rise to these symptoms in schizophrenia.	To the extent that some symptoms of schizophrenia are also evident in other neuropsychiatric disorders, studying these symptoms across disorders can provide some leverage against confounds that tend to be more specific to the schizophrenia spectrum. (e.g. auditory hallucinations can occur in bipolar mania or depression when psychosis accompanies these mood states). Bipolar patients may not have the chronic exposure to anti-psychotic medication typical of schizophrenia, instead being treated with drugs like lithium, valproic acid, and antidepressants. This provides some opportunities to examine symptom correlations with neurobiological measures in bipolar disorder without the confound of dopamine D2 blockade associated with anti-psychotic drugs. Moreover, bipolar patients do not tend to exhibit the negative symptoms or severe functional impairment characteristic of schizophrenia, allowing further dissociation of what tend to be correlated impairments in schizophrenia. Indeed, linking symptoms to brain circuits across traditional diagnostic boundaries has been identified as a major research initiative by NIMH, the so-called Research Domain Criteria (RDoC) initiative. This approach may provide a greater range of variability for specific symptoms and neurobiological abnormalities that can enhance the likelihood of finding significant covariation between them.
Axon Guidance Pathway Genes are Associated With Schizophrenia Risk	Experimental and Therapeutic Medicine	2018	SCZ is a complex polygenic disease, which is associated with many genes and non-coding loci (25). Traditional GWAS analysis has mainly focused on the most significant SNPs that are associated with the pathogenesis of SCZ. Therefore, the less significant genes have not yet been analyzed. They found high degree of repeatability in the genes identified by the two studies and therefore identified 20 candidate pathways associated with SCZ in the two independent SCZ GWAS databases (European and American) from NCBI. They also verified the top three significantly enriched pathways (P<10−4) through pathway analysis of SCZ meta-analysis dataset. The relationship of the axon guidance pathway with SCZ has not been well studied. The aging of human cerebral cortex depends on the proliferation and differentiation of neural progenitor cells, and proper migration and positioning behavior of neurons Disruption in any of these processes can result in aberrant development of the cerebral cortex and is central to many mental illnesses such as SCZ. However, further investigations are necessary to prove this aspect beyond doubt. In our study, we identified two core genes, ROBO2 and DCC, in the axon guidance pathway. Axons integrate directional information multiple guidance cues and their receptors during development. ROBO2 and DCC are axon guidance receptors that can function individually or in combination with other guidance receptors to regulate downstream effectors. DCC is a membrane receptor for Netrin-1, which is mainly expressed in various types of axon beams of the developing central nervous system (CNS). DCC regulates axon guidance, projections, branching and a number of important physiological processes of the CNS neurons after binding to Netrin-1. ROBO2 is a membrane protein that belongs to a class of conserved and development-related transmembrane receptor family roundabout, which promotes axon guidance of embryonic CNS, dendritic branching, axonal growth and neuronal cell migration. ROBO2 cooperates with Slit proteins to guide the major forebrain projections and mainly regulates axon guidance. DCC and ROBO2 as well as their respective ligands, Netrin-1 and Slits, guide the callosum projection neurons across the midline. Glial wedge and indusium griseum represent the main glial cell populations located near the center, which secrete nerve guide factors such as Netrin-1 and Slits. These neural guidance factors interact with their corresponding membrane receptors, DCC and ROBO2, on the neuronal axons projected by the corpus callosum. These processes ensure the axons project correctly and finally form corpus callosum.	Aberrant axon guidance pathway was central to SCZ pathogenesis by combining pathway analysis with less stringent significance criterion in analyzing gene sets from two GWAS. rs9944880 polymorphism in DCC gene on chromosome 18q21.2 was associated with Schizophrenia. From a mechanistic point of view, this polymorphism probably altered the axon guidance pathway resulting in SCZ. In conclusion, our	This study needs to be confirmed in large cohorts of SCZ patients.
Disrupted-in-Schizophrenia 1â€“mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling	Proc Natl Acad Sci U S A. 2011 Apr 5; 108(14): 5861â€“5866.	2011
Autoimmune Diseases and Psychotic Disorders	Frontiers in Psychiatry	2019	The increasing knowledge on the potential involvement of inflammatory processes in mental disorders and the associations found between autoimmunity and psychotic disorders can help the expanding field of immuno-psychiatry and have impact on the outcome of patients. In the last couple of years, researchers have focused on the role of infections, autoantibodies and other immune components that plays a major role in autoimmune diseases. Potentially this might also be the case for mental disorders. Risk factors for both autoimmune diseases and schizophrenia includes an interaction between environmental factors, such as infections and stress, with genetic factors involving the HLA region. Autoimmune reactions with activation of immune components and the production of NSAbs can induce a broad spectrum of psychiatric symptoms, hereunder psychosis. The potential autoimmune-mediated psychosis group might only be a small part of a broader immune-related psychosis group, and an even smaller fraction of the overall psychosis group. However, identification of this subgroup might allow for precision medicine strategies where immune-based treatment could possibly improve the psychotic symptoms. A quick discovery and treatment of autoimmune encephalitis markedly reduces the neuropsychiatric sequelae, and intensive immunotherapy in lupus patients with psychosis massively benefits psychiatric symptoms. Focus on the association between autoimmunity and psychosis, regardless of etiology, is important, not only for researchers but also for the individual patient. t is known that patients suffering from schizophrenia have an excess early mortality, with a life expectancy up to 13.5 years shorter than the general population, primarily due to physical diseases. Bearing this in mind and considering that patients with psychotic disorders might struggle with reporting on somatic symptoms, it is important for clinicians to be aware of an increased prevalence of autoimmune disease in this group. Symptoms from a disease such as celiac disease or rheumatoid arthritis might very well be overlooked and cast aside as a part of the patient's psychosis, or possibly adverse events caused by their treatment. With increasingly sufficient treatment strategies in autoimmune diseases, overlooking and therefore not treating these diseases, increases the health gap between those with schizophrenia and the general population even further. The increasing knowledge on the potential involvement of inflammatory processes in mental disorders and the associations found between autoimmunity and psychotic disorders can help the expanding field of immuno-psychiatry and have impact on the outcome of patients. In the last couple of years, researchers have focused on the role of infections, autoantibodies and other immune components that plays a major role in autoimmune diseases. Potentially this might also be the case for mental disorders. Risk factors for both autoimmune diseases and schizophrenia includes an interaction between environmental factors, such as infections and stress, with genetic factors involving the HLA region. Autoimmune reactions with activation of immune components and the production of NSAbs can induce a broad spectrum of psychiatric symptoms, hereunder psychosis. The potential autoimmune-mediated psychosis group might only be a small part of a broader immune-related psychosis group, and an even smaller fraction of the overall psychosis group. However, identification of this subgroup might allow for precision medicine strategies where immune-based treatment could possibly improve the psychotic symptoms. A quick discovery and treatment of autoimmune encephalitis markedly reduces the neuropsychiatric sequelae, and intensive immunotherapy in lupus patients with psychosis massively benefits psychiatric symptoms.	Patients with a psychotic disorder need to be thoroughly and frequently examined when presenting with symptoms possibly related to autoimmunity or other health problems. Focus on the association between autoimmunity and psychosis, regardless of etiology, is important, not only for researchers but also for the individual patient. It is known that patients suffering from schizophrenia have an excess early mortality, with a life expectancy up to 13.5 years shorter than the general population, primarily due to physical diseases. Bearing this in mind and considering that patients with psychotic disorders might struggle with reporting on somatic symptoms, it is important for clinicians to be aware of an increased prevalence of autoimmune disease in this group. Symptoms from a disease such as celiac disease or rheumatoid arthritis might very well be overlooked and cast aside as a part of the patient's psychosis, or possibly adverse events caused by their treatment. With increasingly sufficient treatment strategies in autoimmune diseases, overlooking and therefore not treating these diseases, increases the health gap between those with schizophrenia and the general population even further. Therefore, patients with a psychotic disorder need to be thoroughly and frequently examined when presenting with symptoms possibly related to autoimmunity or other health problems.	This study discusses the findings on and influence of autoantibodies and dysregulation of T- and B-cells in both disease categories, and why further research hereon is needed. In addition to the potential importance of autoimmunity in etiological mechanisms of psychotic disordershe association also brings important attention to somatic comorbidity in patients with psychotic disorders.
Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases.	Schizophrenia Bulletin	2016	Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity.	There is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin.	Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.
Is schizophrenia an autoimmune disease? A review.	Methods Find Exp Clin Pharmacol.	1984
The Autoimmune and Infectious Etiological Factors of a Subset of Schizophrenia	British Journal of Medical Practitioners	2015	Despite progress in neurotransmitter identifications and the emergence of novel antipsychotics, the treatment of schizophrenia remains frustrating. There is now a flurry of research trying to figure out the aetiology of schizophrenia and potential etiological models other than neurotransmitter dysfunction deserve consideration. Recent years have witnessed a revival of interest in the viral and immunity based etiological models of schizophrenia. There are several commonalities between schizophrenia and autoimmune disorders. Coexistence of established autoimmune disorders along with schizophrenia is suggestive that the latter could also have an autoimmune component. Antipsychotics may be working on the principle of immune modulatory and neuro- modulatory mechanisms. The well recognized 1% global consistency of the incidence of schizophrenia indicates that the aetiology of schizophrenia involve an evolutionary genetic vulnerability and universally present environmental factors. There may be a genetic predisposition to the hypothetical “schizovirus” determining the development of schizophrenia in certain individuals. Certain people are genetically vulnerable to microbial infections in the sense that they have a highly sensitive surveillance system to the microbial infection and respond to the microbial adversary in an exaggerated way. Such a vulnerability and anomalous reaction to infection could result in the schizophrenia psycho-pathogenesis. There are multiple interlinked causative factors in schizophrenia and viral infection may be only a trigger. Viral infections may be the cause of vigorous immune responses or triggering an autoimmune process that lead to neuro-behavioural aberrations and a subset of schizophrenia would emerge as viro-immuno-neuropsychiatric disorder or autoimmuno-neuro-psychiatric disorder. If such a subset of schizophrenia contains an autoimmune component, either triggered by infectious agents or due to unidentified intrinsic factors, the disease process would be determined by genetic vulnerability. Pellagra psychosis due to niacin deficiency was hidden under the schizophrenia umbrella. There may be other psychotic disorders grouped under schizophrenia, and they may have a pure biological aetiology—chemical or infectious—but with genetic vulnerability. No one can be sure whether it is the toxic chemical of the pathogens or the immune response of the host, or both, that may lead to the psychopathology. Searching for this hypothetical virus is a challenging task, but if researchers found it, the benefits would be enormous. A viral aetiology of certain types of schizophrenia, if demonstrable, could affect radical changes in treatment and management. In fact, the hypothesis of viral aetiology is more promising than any other biological hypothesis, as it gives a message of potential drug cure. In this contest, it is interesting to note that the antigenic similarity between components of the streptococcus and cardiac tissue resulted in rheumatic heart diseases, but with the advent of penicillin, this disease has virtually disappeared. Only time will determine the validity and therapeutic prospects of the viral and autoimmune aetiology of schizophrenia.	There is not sufficient evidence established to identify viruses as being implicated in the aetiology of schizophrenia, but researchers have reason to anticipate further laboratory studies, as newer, more sensitive laboratory technologies are evolving. In the last few decades, schizophrenia research has been focussed on neurotransmitter derangements and neuro-developmental anomalies. The cause of a tsunami is not in the sea water, but due to the tectonic shifts under the sea bed; the aetiology of schizophrenia may be similarly due to immune alterations. Davison opined that as evidence accumulates about the autoimmune basis of at least a subset of psychiatric disorders, clinicians should keep abreast of immune-neuropsychiatric research.	While genetic vulnerability has been highlighted in the schizophrenia literature alongside environmental factors, the veracity and contestability of the immunity- and viral-based aetiological hypothesis of schizophrenia merits further investigation. A viral or autoimmune model of schizophrenia may illuminate its pathogenesis, but not necessarily the diversity of psychiatric symptomatology. Psychiatry must constantly expand to meet the growing needs with the emergence of novel ideas in other medical specialities and it is high time to introduce a new terminology—“Psycho-immunovirology”—to study the viral aetiological mechanisms involved in psychiatric disorders like schizophrenia. Neuro-virology and psycho-immuno-virology could develop as an interdisciplinary field which represents a melding of virology, psychiatry, the neurosciences and immunology.
A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis	Journal of Neuroinflammation	2018	This distinction is also therapeutically important as autoimmune-related psychotic symptomatology can frequently respond well to timely treatment with proper immune modulatory therapies. However, building broader consensus evidence-based guidelines highlighting costefficient diagnostic workup and management of patients presenting with unusual new-onset psychotic symptoms with suspected autoimmune origin such as SPAP are warranted. Large-sample randomized clinical trials investigating the prevalence of autoimmune psychosis among individuals with new-onset psychosis are needed. The trial designs need to incorporate more CSF studies and more advanced multi-modal neuroimaging such as resting-state functional brain MRI for elucidating potentially characteristic neural network functional connectivity alterations as well as PET utilizing a novel translocator protein (TSPO) radioligand for imaging microglia activationmediated neuroinflammation.	The suggested etiologically and serologically oriented subclassification as well as the multi-modal diagnostic approach might address some of the challenges inherent to early diagnosis of patients presenting with atypical drug-resistant new-onset psychosis with suspected link to immune dysregulation. This is particularly relevant to the diagnosis of SPAP that might masquerade as antipsychotic drug-resistant primary psychotic disorder.
Systemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions	Schizophrenia Bulletin, Volume 44, Issue 2, March 2018, Pages 398â€“408,	2017	Forty-two articles that met our selection criteria were reviewed. Nearly 75% reported abnormal biomarker levels among individuals with schizophrenia including indices of: Inflammation Cytotoxicity Oxidative stress Metabolic health Gene expression, and Receptor/synaptic function, Twenty-nine percent of the studies observed differential age-related decline in schizophrenia. Markers of receptor/synaptic function and gene expression were most frequently differentially related to age in schizophrenia. Schizophrenia patients with greater disease severity and longer illness duration exhibited higher levels of inflammatory and oxidative stress biomarkers and shorter telomere length	Most studies show biomarker abnormalities in schizophrenia, and there is some suggestion for accelerated aging. Although definitive interpretation is limited by cross-sectional design of the published reports, findings in the area of gene expression and synaptic function are promising and pave the way for future longitudinal studies needed to fully test this hypothesis The jury is still out on the hypothesis of accelerated biological aging in schizophrenia. There is some suggestion for accelerated aging but no clear demonstration.	Confirmation of the hypothesis of accelerated biological aging and identification of relevant biomarkers could help identify high-risk patients and contribute to the development of potentially life-prolonging interventions. Future studies to test the hypothesis of accelerated biological aging should include the following: Longitudinal study designs with a wide range of baseline ages: Structured multi-cohort longitudinal designs are particularly well-suited to address this question.80 With cohort age spans that overlap, age cohort effects can be statistically tested against developmental effects. Longer studies: Schizophrenia is unlike other disorders of aging (eg, Alzheimer’s disease) in which individuals decline rapidly after diagnosis. Trajectories are likely to be considerably slower in schizophrenia and may not be demonstrable with truncated longitudinal follow-up. Larger sample sizes: Given considerable inter-individual variations in biomarker levels, large samples are needed to detect inter-individual variability. Frequent assessments to detect inflection points. Exploration of schizophrenia-specific covariates, such as age of onset, duration of illness, antipsychotic dose, lifetime medication burden, etc. Emphasis on systemic markers of neuronally-relevant gene expression, synaptic function, and antioxidants, as these have the strongest evidence for differential age relationships in cross-sectional studies. An area of particular potential interest and importance is epigenetics, which change with increasing age and contribute to age-related disease.88 DNA methylation has been shown to be a systemic biomarker of biological age, and differences in methylation patterns between an individual’s estimated biological age and chronological age have been shown to be clinically meaningful in various populations.88,89 Only one study has addressed the accelerated biological aging hypothesis in schizophrenia using this approach.90 However, additional studies are needed.
Obstetric Variables Associated With Bipolar Affective Puerperal Psychosis	Br J Psychiatry	2006
Risk of puerperal and non-puerperal recurrence of illness following bipolar affective puerperal (post-partum) psychosis	British Journal of Psychiatry	2005
Accelerated Brain Aging in Schizophrenia: A Longitudinal Pattern Recognition Study	Am J Psychiatry	2016	In schizophrenia patients, brain age was significantly greater than chronological age at baseline (+3.36 years) and progressively increased during follow-up (+1.24 years in addition to the baseline gap). The acceleration of brain aging was not constant: it decreased from 2.5 years/year just after illness onset to about the normal rate (1 year/year) approximately 5 years after illness onset. The schizophrenia gap also increased during follow-up, but more pronounced variability in brain abnormalities at follow-up rendered this increase nonsignificant		The progressive brain loss in schizophrenia appears to reflect two different processes: one relatively homogeneous, reflecting accelerated aging of the brain and related to various measures of outcome, and a more variable one, possibly reflecting individual variation and medication use. Differentiating between these two processes may not only elucidate the various factors influencing brain loss in schizophrenia, but also assist in individualizing treatment.
Lived experience research as a resource for recovery: a mixed methods study					The research suggests the potential usefulness of lived experience research resources, presented in user-friendly formats, in the lives of people who experience mental health issues and implies a need to nurture this type of research.

Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry

Year Published
2018

Discussion / Conclusion / Results

The progress in the genetics of schizophrenia in the last decade has been remarkable.
We used to have not a single known genetic risk variant or gene, and failure to replicate prior reports was the norm.
That was a difficult period for psychiatric genetics investigators that still has consequences to the way some view our field.
Today, we know of numerous robustly supported genetic variants, perhaps more than we hoped for, as well as CNVs, and we have strong evidence for the involvement of rare and de novo variants with stronger effects on the risk.
To allow this progress, large consortia have undertaken the recruitment of cohorts of several thousands of subjects, whose genetic analysis has been made possible by technological advancements.
As this important work continues, it is now time to make sense out of these hundreds of risk factors and see how they can aid the fight against disease.
Creating animal models for schizophrenia based on the results of GWAS is challenging.
The diagnosis in humans is made by interview, which requires verbal interaction, and there is no objectively measurable phenotype such as a laboratory test.
The GWAS variants are mostly non-coding, which limits our ability to accurately recapitulate them in other animals. In addition, even if the effect of the GWAS variants could be accurately mimicked, their resulting increase in risk is so small that such a mutant animal would be unlikely to show a phenotype.
On the other hand, rare variants of larger effect have a level of uncertainty, as most studies report enrichments across many genes rather than definite involvement of individual variants.
Studies in mice have employed knockout or knock-in strategies for a variety of genes with varying degrees of supporting evidence, and have examined schizophrenia-related behavioral domains and phenotypes similar to the endophenotypes described above.
Discussing them is beyond the scope of this review, but there are many other excellent reviews of mouse models, the insights they have provided, and the associated challenges.

Significants of Results

More recently, new approaches to disease models are beginning to show significant promise for schizophrenia research.
The ability to manipulate human cells to induce pluripotency and differentiation and the achievement of accurate and efficient genome editing are advancements that may provide a powerful means to study the biology underlying the risk.
The major advantage is that they allow us to work on a human genomic background and even to create human pluripotent cells that differ only at specific risk variants.
These can be differentiated into the cell type of choice for phenotyping, or even used to generate and study brain organoids.
The applications one can imagine are only limited by what is ethical to do in a lab.
The small effect sizes may still be a problem, but others and we have shown that when one works with modified or edited cells, small effect variants can lead to robust cellular phenotypes.
These technologies are new, and there is still much space for improvement, including editing efficiency, uniform and specific differentiation, the time needed for maturation, and the faithful recapitulation of cortical circuits by organoids
Nevertheless, the genetic findings are there and the tools for us to understand them are rapidly evolving, giving hope for significant breakthroughs within the next decade.
Despite the successes and promise for the future, obstacles in the biological interpretation of GWAS signals in schizophrenia remain. It is significant to know of the genes and variants leading to risk, but given the low odds ratios, it is difficult to measure and resolve their downstream consequences that can lead to disease. W
hile there is no longer doubt these variants, either themselves of those genotypically correlated to them, increase the risk, they are certainly not deterministic and cannot be referred to as causal.
Nevertheless the number of such variants is large and increasing.
Cellular models and genome editing may reveal aspects of their weak effects on neuronal homeostasis, and similarities between them might lead to the perturbed gene networks.
Such discoveries are likely not far down the road and could provide direct targets for intervention.

Recommendations of Future Studies

The agnostic nature of this type of genetics research does not lend itself to evident narratives on the etiology of the disease, which is reflected in this review.
At the same time though, it does not rely on existing knowledge allowing surprising discoveries and breakthroughs.
It might be too early to make up the entire story from the current discoveries but, as opposed to just a decade ago, we are certainly on the way there.

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The Genetics of Schizophrenia

Journal
Research in Translation

Year Published
2017

Discussion / Conclusion / Results

There are good suggestions that these studies have identifi ed plausible candidate genes for schizophrenia. The evidence for several genes involved including DISC1, DTNBP1, NRG1, and RGS4. Each of these genes has received support from multiple lines of evidence with imperfect consistency:

The case for each of these as a candidate gene for schizophrenia is supported by linkage studies
The preponderance of association study findings provides further support
mRNA from each gene is expressed in the prefrontal cortex as well as in other areas of the brain and
Additional neurobiological data link the functions of these genes to biological processes thought to be related to schizophrenia (e.g. DISC1 modulates neurite outgrowth)
There is an extensive literature on the involvement of NRG1 in the development of the CNS,
RGS4 may modulate intracellular signaling for many G-protein-coupled receptors.
DTNBP1 and RGS4 have been reported to be differentially expressed in postmortem brain samples of individuals with schizophrenia.

Significants of Results

This encouraging summation of work in progress masks the lack or consistent replication for the same markers and haplotypes across studies. The literature supports the contention that genetic variation in these genes is associated with schizophrenia, but it lacks impressive consistency in the precise genetic regions and alleles implicated. In contrast, association studies of other complex human genetic diseases have produced unambiguous, consistent, and clear-cut hard replication.

Recommendations of Future Studies

Schizophrenia is hypercomplex and we need to invoke more complicated genetic models than other biomedical disorders.

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The Role of Genetics in the Etiology of Schizophrenia

Discussion / Conclusion / Results

Developments in treatment still lag compared to discoveries of new genetic associations for complex disorders but this situation is expected to change as biological research makes inroads into still purely statistical associations.
There is a strong temptation to accept the simplest observations as the most meaningful and the only ones that merit follow-up.
Research in model organisms shows that most phenotypes are the result of complicated genetic architectures: multiple genes, often showing pleotropy, epistasis and even single mutation effects differing with genetic background and environment
This landscape will probably be true for complex human behavioral traits as well

Significants of Results

Explanations relying on single genes are unlikely to capture the fundamental complexity of most human complex traits, and all the associated genetic variation needs to be pursued to understand the pathophysiology of a complex disorder. A task of utmost importance is the integration of the spectrum of mutations found in schizophrenia into a system that takes into account constantly changing environments and evolution.

Recommendations of Future Studies

It is anticipated that as genetic discoveries accumulate, the application of a myriad of tools from systems biology (e.g., genomics, transcriptomics, proteomics, etc.) will lead to a delineation of biological pathways involved in the pathophysiology of schizophrenia, and eventually to new therapies

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Gene Expression Over the Course of Schizophrenia: From Clinical High-Risk For Psychosis to Chronic Stages

Journal
npj Schizophrenia volume 5, Article number: 5

Year Published
2019

Discussion / Conclusion / Results

MBP and NDEL1 were upregulated in FEP compared to all other groups
DGCR8 was downregulated in FEP compared to HC and CHR
DGCR2 was downregulated in CSZ compared to FEP and HCs
DISC1 was upregulated in schizophrenia compared to controls or FEP, possibly induced by the rs3738398 and rs10864693 genotypes, which were associated with DISC1 expression and
UFD1 was upregulated in CSZ and CHR compared to FEP and HC.

Significants of Results

The results indicate changes in gene expression profiles throughout the different clinical stages of Shizophrenia, reinforcing the need for staging approaches to better capture Schizophrenia heterogeneity. Their findings could be useful for creating a biological signature that is able to predict a psychotic event or help to find adequate treatment and decrease the illness time without a treatment. In this sense, a better characterization of each stage of schizophrenia is essential to improve the understanding of the pathogenesis of the disorder.

Recommendations of Future Studies

There is a need for more predictive markers and an understanding of the biological mechanisms underlying the onset of psychosis.
A better understanding of the biological changes in the different stages of schizophrenia is essential to allow for the identification of these markers,

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Signs of asphyxia at birth and risk of schizophrenia. Population-based case-control study

Journal
Br J Psychiatry. Nov;179:403-8

Year Published
2001

Discussion / Conclusion / Results

There was a strong association between signs of asphyxia at birth and schizophrenia (OR 4.4; 95% C11.9-10.3) after adjustment for other obstetric complications, maternal history of psychotic illness and social class.

Significants of Results

Signs of asphyxia at birth are associated with an increased risk of schizophrenia in adults.
The results support a relationship between hypoxia at birth and schizophrenia, but some of the indicators of foetal disturbance (e.g. pre-eclampsia and prematurity) could not be dismissed as risk factors for schizophrenia.
Disorders (such as pre-eclampsia) could reduce the supply of nutrients, including glucose adn oxygen which would interfere with brain development.
In contrast, an infant who has developed normally may experience relatively short-term insults around the time of birth because of hypoxia
Hypoxic brain damage is particularly seen in the brain-stem nuclei, hippocampus and cortex and is throught to be caused by acidosis and waste products, including amino acids and free radicals
NMDA receptors are considered to play a key role
Reduced volume of hippocampus has recently been described in schizophrenia patients with a history of obstetric complications.

Recommendations of Future Studies

Greater understanding of the effect of hypoxia on brain development adn adult brain function will probably help us to understand more about the pathogenesis of schizophrenia.

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Obstetric Complications and Schizophrenia: Historical and Meta-Analytic Review

Journal
Am J Psychiatry

Year Published
2002

Discussion / Conclusion / Results

The meta-analytic synthesis of the prospective population-based studies revealed that three groups of complications were significantly associated with schizophrenia:

Complications of pregnancy (bleeding, diabetes, rhesus incompatibility, preeclampsia)
Abnormal fetal growth and development: (low birthweight, congenital malformations, reduced head circumference) and
Complications of delivery (uterine atony, asphyxia, emergency Cesarean section).

Current methods for studying the relationship between obstetric complications and schizophrenia merely allow us to report associations and, as a result, we have become stuck at the point of reporting risk factors of “vanishingly small effect” over and over again.

Innovative approaches include the use of animal models to study effects of prenatal infection and the analysis of large cohorts with detailed prenatal data and stored prenatal serum.

As we enter what some researchers have called a new age of epidemiology for schizophrenia, the combination of larger cohorts, new paradigms, and modern statistical and molecular techniques provides the opportunity to discover how obstetric complications contribute to the causation of schizophrenia.

Significants of Results

Current methods of investigating the relationship between obstetric complications and schizophrenia are reaching the limit of their usefulness. Lack of statistical power to measure small and interactive effects and lack of detailed information about the prenatal period are major problems with current approaches.
A combination of disciplines and approaches will be needed to elucidate the mechanisms underlying these small but important associations.

Recommendations of Future Studies

Research in this area will need to move beyond the domain of epidemiology and involve other disciplines (such as developmental biology, neuropathology, and genetics)

Neurobiology of Schizophrenia

Journal
Neuron Volume 52, Issue 1, 5 October

Year Published
2006

Discussion / Conclusion / Results

The molecular genetics of schizophrenia are sufficiently advanced such that etiology-based studies of the neurobiology of schizophrenia are both justified and feasible.
The field is still in its infancy, and we must struggle to integrate our rudimentary knowledge of schizophrenia genetics with our scarcely better developed understanding of normal human brain function.
Additional genetic studies are indispensable in this effort, and will now be facilitated by genome-wide methods for study of association and methods to systematically investigate variations in genomic copy number.
Epigenetic modification, such as methylation, may also prove relevant
Mouse models will make it possible to test pathogenic hypotheses.
The mouse models generated to date have been based on the study of Mendelian disorders
The more subtle etiologies of schizophrenia and other psychiatric disorders may make more complex genetic models important. For instance, it may be important to generate models with splicing alterations in neuregulin 1 or with amino acid polymorphisms in COMT or DISC1.
In addition, it may be important to use inducible or other conditional systems in order to mimic the effect of activation of the genetic lesion in particular tissues at particular times.
In addition to mouse models, genetic models in other organisms may be very useful. Unlike in neurodegenerative diseases, it may be difficult to use Drosophila or other invertebrates as models for the complexities of human psychiatric disorders.
For understanding alterations of cortical development, zebrafish, in which development can be directly visualized, may prove suitable.
Other species with more complex social behaviors and more complex cognition may ultimately be necessary. Perhaps genetically modified primates may become an important source of models, however, human patients must remain the gold standard.

Significants of Results

Mouse models will make it possible to test pathogenic hypotheses.
Studies of genetics and clinical and imaging phenotypes can increasingly be integrated.
DISC1 appears to act as a scaffold for protein interactions, and some of these interacting proteins have altered expression in schizophrenia
These interactors will be helpful for understanding pathogenesis, and can themselves serve as potential candidate genes to test for mutations. Thus, a neurogenetic approach based on candidate genes ) may now become possible.
The DISC1 interacting protein Lis1 is related to lissencephaly, highlighting the idea that schizophrenia, as a subtle disorder of cerebral cortical development, is related to more severe disorders of cerebral cortical development.
Study of the different genetic etiologies of schizophrenia will also improve understanding of the schizophrenia phenotype, and also understanding of affective disorder and potentially other related major psychiatric illnesses, just as study of the different genes causing lissencephaly has allowed a more careful classification of the phenotypes of lissencephaly
Some of the genes, such as dysbindin, appear to be related more specifically to schizophrenia, perhaps especially deficit schizophrenia, while others such as DISC1 and neuregulin 1 can relate to both schizophrenia and affective disorder.
The genes associated with schizophrenia may have a spectrum of different pathogenic effects, altering neuronal development, neuronal plasticity, and signal transduction.
While undoubtedly a great oversimplification, it may be of heuristic value to postulate that variations in particular genes can affect particular neurobiological processes in turn causing specific phenotypes. For instance, effects on neurodevelopment may be more closely associated with schizophrenia, while effects on signal transduction may be more likely to cause affective disorder.

Recommendations of Future Studies

Future imaging studies may be able to combine fMRI with DTI to trace functionally identified circuits.
DISC1 may offer unique opportunities for inroads into understanding the biology of schizophrenia.
DISC1 may serve as a kind of Rosetta Stone for schizophrenia research, helping to connect disparate domains.
Testing these broader hypotheses will require integration of research in:

Biochemistry
Cell biology
Mouse genetics
Neuroimaging and
Human genotype-phenotype correlations.

These studies may allow us to reconceptualize our definitions of the psychiatric disorders, including schizophrenia, based on a better understanding of etiology and pathogenesis.

Neurobiology of Schizophrenia Onset

Journal
Current Top Behaviour Neuroscience

Year Published
Tsung-Ung W. Woo

Discussion / Conclusion / Results

Recent findings suggest that disturbances of a specific subset of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV), which may regulate the course of postnatal developmental experience-dependent synaptic plasticity in the cerebral cortex, including the prefrontal cortex (PFC), may be involved in the pathogenesis of the onset of this illness.
Specifically, converging lines of evidence suggest that oxidative stress, extracellular matrix (ECM) deficit and impaired glutamatergic innervation may contribute to the functional impairment of PV neurons, which may then lead to aberrant developmental synaptic pruning of pyramidal cell circuits during adolescence in the PFC.
In addition to promoting the functional integrity of PV neurons, maturation of ECM may also play an instrumental role in the termination of developmental PFC synaptic pruning; thus, ECM deficit can directly lead to excessive loss of synapses by prolonging the course of pruning.
Together, these mechanisms may contribute to the onset of schizophrenia by compromising the integrity, stability, and fidelity of PFC connectional architecture that is necessary for reliable and predictable information processing.

Recommendations of Future Studies

Further characterization of neurobiological mechanisms will have implications for the conceptualization of rational strategies for the diagnosis, early intervention, and prevention of this debilitating disorder.

Neurobiology of schizophrenia: search for the elusive correlation with symptoms

Journal
Frontiers in Human Neuroscience

Year Published
2012

Discussion / Conclusion / Results

Efforts to find robust correlations between specific symptoms and specific neurobiological measures in schizophrenia would likely achieve more success if such studies employed larger sample sizes where confidence intervals are tighter and spurious correlations are less likely.
The field needs to make advances in the measurement of symptoms, going beyond the retrospective interview-based ratings of one or a few items that typify the approach taken in current studies.
Examples of such approaches include multi-item ratings scales for hallucinations like the psychotic symptom rating scale, real-time event sampling to reduce the reliance on patient’s retrospective accounts of their symptoms, and assessments of symptoms at multiple time points over the illness course to facilitate the distinction between trait- and state-related variation in symptom severity.
Finally, greater emphasis needs to be placed on accurate estimation of the reliability of symptom measurements, as well as the reliability of the neurobiological measures that are correlated with symptom severity.
Studies of medication naïve first-episode patients is a potentially useful strategy for capturing variation in primary symptom severity with the confounding effects of medication, but such patients are difficult to recruit and the duration of time that medication can be ethically withheld is fairly limited.
Moreover, to the extent that schizophrenia involves a progressive pathophysiology over the illness course, symptom correlations present at the onset of illness may not hold for chronic patients.
That symptoms may depend on the stage of illness is supported by studies that suggest that positive symptoms become less severe and negative symptoms more prominent in the later stages of schizophrenia
In addition, studying samples of schizophrenia patients who have transiently discontinued their medication or who choose not to take medication is another approach to capturing symptom variation in the absence of medication confounds.
However, this approach may not yield symptom correlations that generalize to the entire population of schizophrenia patients, particularly to the extent that chronic patients who can live independently in the community without medication may not be representative of schizophrenia patients in general.
One strategy that attempts to overcome the limitations of correlational brain-symptom data in clinical research studies is to use pharmacological challenges with agents that affect specific neuroreceptors in order to transiently exacerbate symptoms in patients, or to transiently induce schizophrenia-like symptoms in healthy volunteers.
This strategy is exemplified by the use of the NMDA-receptor antagonist, ketamine, in challenge studies with patients and healthy volunteers, to test the hypothesis that NMDA-receptor hypofunction contributes to both clinical symptoms and neurocognitive deficits in schizophrenia.
Another promising approach to overcoming the correlation–causation conundrum that is still in its early stages of development is the use of transcranial magnetic stimulation (TMS) to transiently perturb specific brain regions and circuits.
While repetitive TMS has already been studied as a potential treatment for auditory hallucinations, the possibility of using TMS targeted at specific brain regions to transiently increase or decrease specific symptoms in order to provide evidence for the causal role of that brain region in producing or modulating the symptom remains largely unexplored.
Nonetheless, both the pharmacological probe and the TMS probe approach to establishing causal connections between brain function and specific symptoms have some conceptual limitations.
In particular, even if manipulating brain function with these methods can reproduce schizophrenia-like symptoms, this does not preclude the possibility that distinctly different pathophysiological mechanisms give rise to these symptoms in schizophrenia.

Significants of Results

To the extent that some symptoms of schizophrenia are also evident in other neuropsychiatric disorders, studying these symptoms across disorders can provide some leverage against confounds that tend to be more specific to the schizophrenia spectrum. (e.g. auditory hallucinations can occur in bipolar mania or depression when psychosis accompanies these mood states).
Bipolar patients may not have the chronic exposure to anti-psychotic medication typical of schizophrenia, instead being treated with drugs like lithium, valproic acid, and antidepressants.
This provides some opportunities to examine symptom correlations with neurobiological measures in bipolar disorder without the confound of dopamine D2 blockade associated with anti-psychotic drugs.
Moreover, bipolar patients do not tend to exhibit the negative symptoms or severe functional impairment characteristic of schizophrenia, allowing further dissociation of what tend to be correlated impairments in schizophrenia.
Indeed, linking symptoms to brain circuits across traditional diagnostic boundaries has been identified as a major research initiative by NIMH, the so-called Research Domain Criteria (RDoC) initiative.
This approach may provide a greater range of variability for specific symptoms and neurobiological abnormalities that can enhance the likelihood of finding significant covariation between them.

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Axon Guidance Pathway Genes are Associated With Schizophrenia Risk

Journal
Experimental and Therapeutic Medicine

Year Published
2018

Discussion / Conclusion / Results

SCZ is a complex polygenic disease, which is associated with many genes and non-coding loci (25).
Traditional GWAS analysis has mainly focused on the most significant SNPs that are associated with the pathogenesis of SCZ. Therefore, the less significant genes have not yet been analyzed.
They found high degree of repeatability in the genes identified by the two studies and therefore identified 20 candidate pathways associated with SCZ in the two independent SCZ GWAS databases (European and American) from NCBI.
They also verified the top three significantly enriched pathways (P<10−4) through pathway analysis of SCZ meta-analysis dataset.
The relationship of the axon guidance pathway with SCZ has not been well studied.
The aging of human cerebral cortex depends on the proliferation and differentiation of neural progenitor cells, and proper migration and positioning behavior of neurons
Disruption in any of these processes can result in aberrant development of the cerebral cortex and is central to many mental illnesses such as SCZ. However, further investigations are necessary to prove this aspect beyond doubt.
In our study, we identified two core genes, ROBO2 and DCC, in the axon guidance pathway.
Axons integrate directional information multiple guidance cues and their receptors during development. ROBO2 and DCC are axon guidance receptors that can function individually or in combination with other guidance receptors to regulate downstream effectors.
DCC is a membrane receptor for Netrin-1, which is mainly expressed in various types of axon beams of the developing central nervous system (CNS). DCC regulates axon guidance, projections, branching and a number of important physiological processes of the CNS neurons after binding to Netrin-1.
ROBO2 is a membrane protein that belongs to a class of conserved and development-related transmembrane receptor family roundabout, which promotes axon guidance of embryonic CNS, dendritic branching, axonal growth and neuronal cell migration.
ROBO2 cooperates with Slit proteins to guide the major forebrain projections and mainly regulates axon guidance.
DCC and ROBO2 as well as their respective ligands, Netrin-1 and Slits, guide the callosum projection neurons across the midline.
Glial wedge and indusium griseum represent the main glial cell populations located near the center, which secrete nerve guide factors such as Netrin-1 and Slits.
These neural guidance factors interact with their corresponding membrane receptors, DCC and ROBO2, on the neuronal axons projected by the corpus callosum.
These processes ensure the axons project correctly and finally form corpus callosum.

Significants of Results

Aberrant axon guidance pathway was central to SCZ pathogenesis by combining pathway analysis with less stringent significance criterion in analyzing gene sets from two GWAS.
rs9944880 polymorphism in DCC gene on chromosome 18q21.2 was associated with Schizophrenia.
From a mechanistic point of view, this polymorphism probably altered the axon guidance pathway resulting in SCZ. In conclusion, our

Recommendations of Future Studies

This study needs to be confirmed in large cohorts of SCZ patients.

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Disrupted-in-Schizophrenia 1â€“mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Journal
Proc Natl Acad Sci U S A. 2011 Apr 5; 108(14): 5861â€“5866.

Year Published
2011

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Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychiatry

Year Published
2019

Discussion / Conclusion / Results

The increasing knowledge on the potential involvement of inflammatory processes in mental disorders and the associations found between autoimmunity and psychotic disorders can help the expanding field of immuno-psychiatry and have impact on the outcome of patients.
In the last couple of years, researchers have focused on the role of infections, autoantibodies and other immune components that plays a major role in autoimmune diseases.
Potentially this might also be the case for mental disorders.
Risk factors for both autoimmune diseases and schizophrenia includes an interaction between environmental factors, such as infections and stress, with genetic factors involving the HLA region.
Autoimmune reactions with activation of immune components and the production of NSAbs can induce a broad spectrum of psychiatric symptoms, hereunder psychosis.
The potential autoimmune-mediated psychosis group might only be a small part of a broader immune-related psychosis group, and an even smaller fraction of the overall psychosis group. However, identification of this subgroup might allow for precision medicine strategies where immune-based treatment could possibly improve the psychotic symptoms.
A quick discovery and treatment of autoimmune encephalitis markedly reduces the neuropsychiatric sequelae, and intensive immunotherapy in lupus patients with psychosis massively benefits psychiatric symptoms.
Focus on the association between autoimmunity and psychosis, regardless of etiology, is important, not only for researchers but also for the individual patient. t is known that patients suffering from schizophrenia have an excess early mortality, with a life expectancy up to 13.5 years shorter than the general population, primarily due to physical diseases.
Bearing this in mind and considering that patients with psychotic disorders might struggle with reporting on somatic symptoms, it is important for clinicians to be aware of an increased prevalence of autoimmune disease in this group.
Symptoms from a disease such as celiac disease or rheumatoid arthritis might very well be overlooked and cast aside as a part of the patient's psychosis, or possibly adverse events caused by their treatment.
With increasingly sufficient treatment strategies in autoimmune diseases, overlooking and therefore not treating these diseases, increases the health gap between those with schizophrenia and the general population even further.
The increasing knowledge on the potential involvement of inflammatory processes in mental disorders and the associations found between autoimmunity and psychotic disorders can help the expanding field of immuno-psychiatry and have impact on the outcome of patients.
In the last couple of years, researchers have focused on the role of infections, autoantibodies and other immune components that plays a major role in autoimmune diseases.
Potentially this might also be the case for mental disorders.
Risk factors for both autoimmune diseases and schizophrenia includes an interaction between environmental factors, such as infections and stress, with genetic factors involving the HLA region.
Autoimmune reactions with activation of immune components and the production of NSAbs can induce a broad spectrum of psychiatric symptoms, hereunder psychosis.
The potential autoimmune-mediated psychosis group might only be a small part of a broader immune-related psychosis group, and an even smaller fraction of the overall psychosis group.
However, identification of this subgroup might allow for precision medicine strategies where immune-based treatment could possibly improve the psychotic symptoms.
A quick discovery and treatment of autoimmune encephalitis markedly reduces the neuropsychiatric sequelae, and intensive immunotherapy in lupus patients with psychosis massively benefits psychiatric symptoms.

Significants of Results

Patients with a psychotic disorder need to be thoroughly and frequently examined when presenting with symptoms possibly related to autoimmunity or other health problems.
Focus on the association between autoimmunity and psychosis, regardless of etiology, is important, not only for researchers but also for the individual patient. It is known that patients suffering from schizophrenia have an excess early mortality, with a life expectancy up to 13.5 years shorter than the general population, primarily due to physical diseases.
Bearing this in mind and considering that patients with psychotic disorders might struggle with reporting on somatic symptoms, it is important for clinicians to be aware of an increased prevalence of autoimmune disease in this group.
Symptoms from a disease such as celiac disease or rheumatoid arthritis might very well be overlooked and cast aside as a part of the patient's psychosis, or possibly adverse events caused by their treatment.
With increasingly sufficient treatment strategies in autoimmune diseases, overlooking and therefore not treating these diseases, increases the health gap between those with schizophrenia and the general population even further.
Therefore, patients with a psychotic disorder need to be thoroughly and frequently examined when presenting with symptoms possibly related to autoimmunity or other health problems.

Recommendations of Future Studies

This study discusses the findings on and influence of autoantibodies and dysregulation of T- and B-cells in both disease categories, and why further research hereon is needed.
In addition to the potential importance of autoimmunity in etiological mechanisms of psychotic disordershe association also brings important attention to somatic comorbidity in patients with psychotic disorders.

Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases.

Journal
Schizophrenia Bulletin

Year Published
2016

Discussion / Conclusion / Results

Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain.
While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility.
Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity.

Significants of Results

There is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin.

Recommendations of Future Studies

Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.

Is schizophrenia an autoimmune disease? A review.

Journal
Methods Find Exp Clin Pharmacol.

Year Published
1984

The Autoimmune and Infectious Etiological Factors of a Subset of Schizophrenia

Journal
British Journal of Medical Practitioners

Year Published
2015

Discussion / Conclusion / Results

Despite progress in neurotransmitter identifications and the emergence of novel antipsychotics, the treatment of schizophrenia remains frustrating.
There is now a flurry of research trying to figure out the aetiology of schizophrenia and potential etiological models other than neurotransmitter dysfunction deserve consideration.
Recent years have witnessed a revival of interest in the viral and immunity based etiological models of schizophrenia.
There are several commonalities between schizophrenia and autoimmune disorders.
Coexistence of established autoimmune disorders along with schizophrenia is suggestive that the latter could also have an autoimmune component.
Antipsychotics may be working on the principle of immune modulatory and neuro- modulatory mechanisms.
The well recognized 1% global consistency of the incidence of schizophrenia indicates that the aetiology of schizophrenia involve an evolutionary genetic vulnerability and universally present environmental factors.
There may be a genetic predisposition to the hypothetical “schizovirus” determining the development of schizophrenia in certain individuals.
Certain people are genetically vulnerable to microbial infections in the sense that they have a highly sensitive surveillance system to the microbial infection and respond to the microbial adversary in an exaggerated way.
Such a vulnerability and anomalous reaction to infection could result in the schizophrenia psycho-pathogenesis.
There are multiple interlinked causative factors in schizophrenia and viral infection may be only a trigger.
Viral infections may be the cause of vigorous immune responses or triggering an autoimmune process that lead to neuro-behavioural aberrations and a subset of schizophrenia would emerge as viro-immuno-neuropsychiatric disorder or autoimmuno-neuro-psychiatric disorder.
If such a subset of schizophrenia contains an autoimmune component, either triggered by infectious agents or due to unidentified intrinsic factors, the disease process would be determined by genetic vulnerability.
Pellagra psychosis due to niacin deficiency was hidden under the schizophrenia umbrella.
There may be other psychotic disorders grouped under schizophrenia, and they may have a pure biological aetiology—chemical or infectious—but with genetic vulnerability. No one can be sure whether it is the toxic chemical of the pathogens or the immune response of the host, or both, that may lead to the psychopathology.
Searching for this hypothetical virus is a challenging task, but if researchers found it, the benefits would be enormous.
A viral aetiology of certain types of schizophrenia, if demonstrable, could affect radical changes in treatment and management. In fact, the hypothesis of viral aetiology is more promising than any other biological hypothesis, as it gives a message of potential drug cure. In this contest, it is interesting to note that the antigenic similarity between components of the streptococcus and cardiac tissue resulted in rheumatic heart diseases, but with the advent of penicillin, this disease has virtually disappeared. Only time will determine the validity and therapeutic prospects of the viral and autoimmune aetiology of schizophrenia.

Significants of Results

There is not sufficient evidence established to identify viruses as being implicated in the aetiology of schizophrenia, but researchers have reason to anticipate further laboratory studies, as newer, more sensitive laboratory technologies are evolving. In the last few decades, schizophrenia research has been focussed on neurotransmitter derangements and neuro-developmental anomalies.
The cause of a tsunami is not in the sea water, but due to the tectonic shifts under the sea bed; the aetiology of schizophrenia may be similarly due to immune alterations.
Davison opined that as evidence accumulates about the autoimmune basis of at least a subset of psychiatric disorders, clinicians should keep abreast of immune-neuropsychiatric research.

Recommendations of Future Studies

While genetic vulnerability has been highlighted in the schizophrenia literature alongside environmental factors, the veracity and contestability of the immunity- and viral-based aetiological hypothesis of schizophrenia merits further investigation.
A viral or autoimmune model of schizophrenia may illuminate its pathogenesis, but not necessarily the diversity of psychiatric symptomatology.
Psychiatry must constantly expand to meet the growing needs with the emergence of novel ideas in other medical specialities and it is high time to introduce a new terminology—“Psycho-immunovirology”—to study the viral aetiological mechanisms involved in psychiatric disorders like schizophrenia.
Neuro-virology and psycho-immuno-virology could develop as an interdisciplinary field which represents a melding of virology, psychiatry, the neurosciences and immunology.

A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis

Journal
Journal of Neuroinflammation

Year Published
2018

Discussion / Conclusion / Results

This distinction is also therapeutically important as autoimmune-related psychotic symptomatology can frequently respond well to timely treatment with proper immune modulatory therapies.
However, building broader consensus evidence-based guidelines highlighting costefficient diagnostic workup and management of patients presenting with unusual new-onset psychotic symptoms with suspected autoimmune origin such as SPAP are warranted.
Large-sample randomized clinical trials investigating the prevalence of autoimmune psychosis among individuals with new-onset psychosis are needed.
The trial designs need to incorporate more CSF studies and more advanced multi-modal neuroimaging such as resting-state functional brain MRI for elucidating potentially characteristic neural network functional connectivity alterations as well as PET utilizing a novel translocator protein (TSPO) radioligand for imaging microglia activationmediated neuroinflammation.

Significants of Results

The suggested etiologically and serologically oriented subclassification as well as the multi-modal diagnostic approach might address some of the challenges inherent to early diagnosis of patients presenting with atypical drug-resistant new-onset psychosis with suspected link to immune dysregulation.
This is particularly relevant to the diagnosis of SPAP that might masquerade as antipsychotic drug-resistant primary psychotic disorder.

Systemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions

Journal
Schizophrenia Bulletin, Volume 44, Issue 2, March 2018, Pages 398â€“408,

Year Published
2017

Discussion / Conclusion / Results

Forty-two articles that met our selection criteria were reviewed.
Nearly 75% reported abnormal biomarker levels among individuals with schizophrenia including indices of:

Inflammation
Cytotoxicity
Oxidative stress
Metabolic health
Gene expression, and
Receptor/synaptic function,

Twenty-nine percent of the studies observed differential age-related decline in schizophrenia.
Markers of receptor/synaptic function and gene expression were most frequently differentially related to age in schizophrenia.
Schizophrenia patients with greater disease severity and longer illness duration exhibited higher levels of inflammatory and oxidative stress biomarkers and shorter telomere length

Significants of Results

Most studies show biomarker abnormalities in schizophrenia, and there is some suggestion for accelerated aging.
Although definitive interpretation is limited by cross-sectional design of the published reports, findings in the area of gene expression and synaptic function are promising and pave the way for future longitudinal studies needed to fully test this hypothesis
The jury is still out on the hypothesis of accelerated biological aging in schizophrenia. There is some suggestion for accelerated aging but no clear demonstration.

Recommendations of Future Studies

Confirmation of the hypothesis of accelerated biological aging and identification of relevant biomarkers could help identify high-risk patients and contribute to the development of potentially life-prolonging interventions. Future studies to test the hypothesis of accelerated biological aging should include the following:

Longitudinal study designs with a wide range of baseline ages: Structured multi-cohort longitudinal designs are particularly well-suited to address this question.80 With cohort age spans that overlap, age cohort effects can be statistically tested against developmental effects.
Longer studies: Schizophrenia is unlike other disorders of aging (eg, Alzheimer’s disease) in which individuals decline rapidly after diagnosis. Trajectories are likely to be considerably slower in schizophrenia and may not be demonstrable with truncated longitudinal follow-up.
Larger sample sizes: Given considerable inter-individual variations in biomarker levels, large samples are needed to detect inter-individual variability.
Frequent assessments to detect inflection points.
Exploration of schizophrenia-specific covariates, such as age of onset, duration of illness, antipsychotic dose, lifetime medication burden, etc.
Emphasis on systemic markers of neuronally-relevant gene expression, synaptic function, and antioxidants, as these have the strongest evidence for differential age relationships in cross-sectional studies. An area of particular potential interest and importance is epigenetics, which change with increasing age and contribute to age-related disease.88 DNA methylation has been shown to be a systemic biomarker of biological age, and differences in methylation patterns between an individual’s estimated biological age and chronological age have been shown to be clinically meaningful in various populations.88,89 Only one study has addressed the accelerated biological aging hypothesis in schizophrenia using this approach.90 However, additional studies are needed.

Full Article
../../dc/studies-full-article/SystemicZBiomarkersZofZAcceleratedZAgingZinZSchizophrenia.pdf

Obstetric Variables Associated With Bipolar Affective Puerperal Psychosis

Journal
Br J Psychiatry

Year Published
2006

Full Article
../../dc/studies-full-article/obstetric-variables-associated-with-bipolar-affective-puerperal-psychosis.pdf

Risk of puerperal and non-puerperal recurrence of illness following bipolar affective puerperal (post-partum) psychosis

Journal
British Journal of Psychiatry

Year Published
2005

Full Article
../../dc/studies-full-article/risk-of-puerperal-and-non-puerperal-recurrence-of-illness-following-bipolar-affective-puerperal-post-partum-psychosis.pdf

Accelerated Brain Aging in Schizophrenia: A Longitudinal Pattern Recognition Study

Journal
Am J Psychiatry

Year Published
2016

Discussion / Conclusion / Results

In schizophrenia patients, brain age was significantly greater than chronological age at baseline (+3.36 years) and progressively increased during follow-up (+1.24 years in addition to the baseline gap).
The acceleration of brain aging was not constant: it decreased from 2.5 years/year just after illness onset to about the normal rate (1 year/year) approximately 5 years after illness onset.
The schizophrenia gap also increased during follow-up, but more pronounced variability in brain abnormalities at follow-up rendered this increase nonsignificant

Recommendations of Future Studies

The progressive brain loss in schizophrenia appears to reflect two different processes: one relatively homogeneous, reflecting accelerated aging of the brain and related to various measures of outcome, and a more variable one, possibly reflecting individual variation and medication use.
Differentiating between these two processes may not only elucidate the various factors influencing brain loss in schizophrenia, but also assist in individualizing treatment.

Full Article
../../dc/studies-full-article/AcceleratedZBrainZAgingZinZSchizophrenia.pdf

Lived experience research as a resource for recovery: a mixed methods study

Recommendations of Future Studies

The research suggests the potential usefulness of lived experience research resources, presented in user-friendly formats, in the lives of people who experience mental health issues and implies a need to nurture this type of research.

Full Article
../../dc/studies-full-article/s12888-020-02861-0.pdf

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