Hanson DR, Gottesman II. Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Genet 6: 7

Department of Psychiatry, VA Medical Center (116A), One Veterans Drive, Minneapolis, MN 55417, USA.
BMC Medical Genetics (Impact Factor: 2.08). 03/2005; 6(1):7. DOI: 10.1186/1471-2350-6-7
Source: PubMed


Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease.
A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems.
A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons.

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    • "As an example, multiple sclerosis (MS) is an inflammatory disease of the CNS that shows a relapsing-remitting course and, in a certain percentage of patients, also a chronic, progressive course. Parallels between MS and schizophrenia, which also often shows a chronic course, have repeatedly been highlighted as arguments for similar pathogenetic mechanisms in these disorders (Hanson and Gottesman, 2005). The concept of " smoldering inflammation " implies that CNS inflammation drives the disease process in both acute and chronic stages (Kutzelnigg et al., 2005). "
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    ABSTRACT: Abstract High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis
    Full-text · Article · Nov 2015 · Frontiers in Neuroscience
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    • "Increasing evidence indicates that inflammation is involved in the pathogenesis of schizophrenia ( Hanson and Gottesman , 2005 ) . Prenatal infection and maternal immune alterations during preg - nancy have been linked to the risk of schizophrenia ( Brown , 2006 ; Ellman et al . "
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    ABSTRACT: Objective: Increasing the evidence of inflammation's contribution to schizophrenia; using anti-inflammatory or neurotrophic therapeutic agents to see whether they improve schizophrenia treatment. Dextromethorphan (DM), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, might protect monoamine neurons. Whether treating schizophrenia with risperidone plus add-on DM is more effective than risperidone (RISP) alone, and the association between the ALDH2 polymorphism and treatment response were investigated. Methods: A double-blind study in which patients with schizophrenia were randomly assigned to the RISP + DM (60 mg/day; n = 74) or the RISP + Placebo (n = 75) group. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) scores were used to evaluate clinical response during weeks 0, 1, 2, 4, 6, 8, and 11. The genotypes of the ALDH2 polymorphism were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. A generalized estimating equation was used to analyze the effects of ALDH2 polymorphism on the clinical performance of DM. Results: PANSS and SANS scores were significantly lower in both groups after 11 weeks of treatment. SANS total scores were significantly lower in the RISP + DM group in patients with the ALDH2*2*2 genotype. Conclusions: RISP plus add-on DM treatment reduced negative schizophrenia symptoms in patients with the ALDH2 polymorphism.
    Full-text · Article · Sep 2015 · Journal of Psychiatric Research
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    • "Inflammation within the CNS contributes to many acute and chronic degenerative disorders such as PD and AD [Gonzalez-Scarano and Baltuch, 1999]. Inflammation is also under study for a role in the onset of some psychiatric diseases (i.e., depression, post-traumatic stress disorder [PTSD], schizophrenia) [Hanson & Gottesman, 2005; Dantzer et al., 2008]. The antiinflammatory function of PPARg has attracted many attentions since its agonists exert a broad spectrum of protective effects in several animal models of neurological diseases (AD, multiple sclerosis) [Feinstein, 2003]. "

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