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Causes of schizophrenia

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Structural

Studies have tended to show various subtle average differences in the volume of certain areas of brain structure between people with and without diagnoses of schizophrenia, although it has become increasingly clear that there is no single pathological neuropsychological or structural neuroanatomic profile, due partly to heterogeneity within the disorder. The most consistent volumetric findings are (first-onset patient vs control group averages), slightly less grey matter volume and slightly increased ventricular volume in certain areas of the brain. The two findings are thought to be linked. Although the differences are found in first-episode cases, grey matter volumes are partly a result of life experiences, drugs and malnutrition etc., so the exact role in the disorder is unclear. In addition, ventricle volumes are amongst the mostly highly variable and environmentally influenced aspects of brain structure, and the percentage difference in group averages in schizophrenia studies has been described as "not a very profound difference in the context of normal variation." A slightly smaller than average whole-brain volume has also been also been found, and slightly smaller hippocampal volume in terms of group averages. These differences may be present from birth or develop later, and there is substantial variation between individuals.

Most schizophrenia studies have found average reduced volume of the left medial temporal lobe and left superior temporal gyrus, and half of studies have revealed deficits in certain areas of the frontal gyrus, parahippocampal gyrus and temporal gyrus. However, at variance with some findings in individuals with chronic schizophrenia (where use of antipsychotics and other factors may have a confounding effect), significant group differences of temporal lobe and amygdala volumes are not shown in first-episode patients on average. The neurobiological abnormalities are so varied that no single abnormality is observed across the entire group of people with DSM-IV–defined schizophrenia. In addition, it remains unclear whether the structural differences are unique to schizophrenia or cut across the traditional diagnostic boundaries between schizophrenia and affective disorders - though perhaps being unique to conditions with psychotic features.

Studies of the rare childhood-onset schizophrenia (before age 13) indicate a greater-than-normal loss of grey matter over several years, progressing from the back of the brain to the front, levelling out in early adulthood. Such a pattern of "pruning" occurs as part of normal brain development but appears to be exaggerated in childhood-onset psychotic diagnoses, particularly schizophrenia. Abnormalities in the volume of the ventricles or frontal lobes have also been found in several studies but not in others. Volume changes are most likely glial and vascular rather than purely neuronal, and reduction in grey matter may primarily reflect a reduction of neuropil rather than a deficit in the total number of neurons. Other studies, especially some computational studies, have shown that a reduction in the number of neurons can cause psychotic symptoms. Studies to date have been based on small numbers of the most severe and treatment-resistant patients taking antipsychotics.

Functional

Functional magnetic resonance imaging and other brain imaging technologies allow for the study of differences in brain activity among people diagnosed with schizophrenia.

Some studies using neuropsychological tests and brain imaging technologies such as fMRI and PET to examine functional differences in brain activity have shown that differences seem to most commonly occur in the frontal lobes, hippocampus, and temporal lobes. Abnormalities of the kind shown are linked to the same neurocognitive deficits often associated with schizophrenia, particularly in areas of memory, attention, problem solving, executive function, and social cognition. Observations of the frontal lobe in patients with schizophrenia are inconsistent: While many studies have found abnormalities, others have found no or only a statistically insignificant difference. Data from a PET study suggests that the less the frontal lobes are activated during a working memory task, the greater the increase in abnormal dopamine activity in the striatum, thought to be related to the neurocognitive deficits in schizophrenia.

Electroencephalograph (EEG) recordings of persons with schizophrenia performing perception oriented tasks showed an absence of gamma band activity in the brain, indicating weak integration of critical neural networks in the brain. Those who experienced intense hallucinations, delusions and disorganized thinking showed the lowest frequency synchronization. None of the drugs taken by the persons scanned had moved neural synchrony back into the gamma frequency range. Gamma band and working memory alterations may be related to alterations in interneurons that produce the neurotransmitter GABA.

Atypical connectivity in the default network and other resting-state networks in the brain has been observed in schizophrenic patients. The greater connectivity in the default network and the task-positive network may reflect excessive orientation of attention to introspection and to extrospection, respectively, and the greater anti-correlation between the two networks suggests excessive rivalry between the networks. Increased deactivation of specific default-network regions is associated with the positive symptoms of schizophrenia.

Dopamine

Main article: Dopamine hypothesis of schizophrenia
Dopamine D2-Like Sites in Schizophrenia, But Not in Alzheimer’s, Huntington’s, or Control Brains for Benzquinoline;Synapse Vol 25 1997; pp137–146, ; copyright 1997 PHILIP SEEMAN, HONG-CHANG GUAN, JOSE NOBREGA, DILSHAD JIWA, RUDOLPH MARKSTEIN, JA-HYUN BALK, ROBERTO PICETTI, EMILIANA BORRELLI, AND HUBERT H.M. VAN TOL Reprinted with permission of John Wiley & Sons, Inc.No rights are granted to use content that appears in the work with credit to another source. The authors say the d2-like sites detected in this diagram could represent the d4-like sites in other replicated experiments and that these are probably d2 monomers. In the 1997 report, Dr Seeman said more research had to be done into the receptors which were marked by GLC 756. Whatever the sites, there is something profoundly different between schizophrenic and other cases. Dr Seeman's decision to call the site dopaminergic was: "Because dopamine was much more effective than norepinephrine or serotonin , the binding site was considered dopaminergic". A 2006 journal reports GLC756 measures: D1, D2, D4, TFNα-1, α-2, 5-HT1A, 5-HT2C, 5-HT1D, 5-HT2 A, adrenoceptors β-1, and β-2 - Dr Seeman tested for all groups by their neurotransmitter (fig 3) except transferrin A crucial part of the method was to measure for non-specific binding. This wasn't done in negative experiments.

Particular focus has been placed upon the function of dopamine in the mesolimbic pathway of the brain. This focus largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, could reduce psychotic symptoms. An influential theory, known as the "dopamine hypothesis of schizophrenia", proposed that a malfunction involving dopamine pathways was therefore the cause of (the positive symptoms of) schizophrenia. Evidence for this theory includes findings that the potency of many antipsychotics is correlated with their affinity to dopamine D2 receptors; and the exacerbatory effects of a dopamine agonist (amphetamine) and a dopamine beta hydroxylase inhibitor (disulfiram) on schizophrenia; and post-mortem studies initially suggested increased density of dopamine D2 receptors in the striatum. Such high levels of D receptors intensify brain signals in schizophrenia and causes positive symptoms such as hallucinations and paranoia. Impaired glutamate (a neurotransmitter which directs neuron to pass along an impulse) activity appears to be another source of schizophrenia symptoms.

However, there was controversy and conflicting findings over whether post-mortem findings resulted from chronic antipsychotic treatment. Compared to the success of postmortem studies in finding profound changes of dopamine receptors, imaging studies using SPET and PET methods in drug naive patients have generally failed to find any difference in dopamine D2 receptor density compared to controls. Comparable findings in longitudinal studies show: " Particular emphasis is given to methodological limitations in the existing literature, including lack of reliability data, clinical heterogeneity among studies, and inadequate study designs and statistic," suggestions are made for improving future longitudinal neuroimaging studies of treatment effects in schizophrenia A recent review of imaging studies in schizophrenia shows confidence in the techniques, while disussing such operator error. In 2007 one report said, "During the last decade, results of brain imaging studies by use of PET and SPET in schizophrenic patients showed a clear dysregulation of the dopaminergic system."

Recent findings from meta-analyses suggest that there may be a small elevation in dopamine D2 receptors in drug-free patients with schizophrenia, but the degree of overlap between patients and controls makes it unlikely that this is clinically meaningful. In addition, newer antipsychotic medication (called atypical antipsychotic medication) can be as potent as older medication (called typical antipsychotic medication) while also affecting serotonin function and having somewhat less of a dopamine blocking effect. In addition, dopamine pathway dysfunction has not been reliably shown to correlate with symptom onset or severity. HVA levels correlate trendwise to symptoms severity. During the application of debrisoquin this correlation becomes significant

Giving a more precise explanation of this discrepancy in d2 receptor radioligand imaging measurements involves the monomer and dimer ratio, Dr Philip Seeman has said: "In schizophrenia, therefore, the density of methylspiperone sites rises, reflecting an increase in monomers, while the density of raclopride sites remains the same, indicating that the total population of D2 monomers and dimers does not change.". With this difference in measurement technique in mind; the above mentioned meta analysis uses results from 10 different ligands.

It has been said that, "...Numerous postmortem studies have consistently revealed D2 receptors to be elevated in the striata of patients with schizophrenia". However, the authors were concerned the effect of medication may not have been fully accounted for. The study introduced an experiment by Abi-Dargham et al. in which it was shown medication free live schizophrenics had more d2 receptors involved in the schizophrenic process and more dopamine. Since then another study has shown such elevated percentages in d2 receptors is brain-wide (using a different ligand, which did not need dopamine depletion) In a 2009 study Annisa Abi-Dagham et al. confirmed the findings of her previous study regarding increased baseline d2 receptors in schizophrenics and showing a correlation between this magnitude and the result of amphetamine stimulation experiments.

Some animal models of psychosis are similar to those for addiction - displaying increased locomotor activity For those female animals with previous sexual experience, amphetamine stimulation happens faster than for virgins. There is no study on male equivalent because the studies are meant to explain why females experience addiction earlier than males.

Even in 1986 the effect of antipsychotics on receptor measurement was controversial. An article in Science sought to clarify whether the increase was solely due to medication by using drug naive schizophrenics: "The finding that D2 dopamine receptors are substantially increased in schizophrenic patients who have never been treated with neuroleptic drugs raises the possibility that dopamine receptors are involved in the schizophrenic disease process itself. Alternatively, the increased D2 receptor number may reflect presynaptic factors such as increased endogenous dopamine levels (16). In either case, our findings support the hypothesis that dopamine receptor abnormalities are present in untreated schizophrenic patients." (The experiment used 3-N-methylspiperone- the same as mentioned by Dr Seeman detects d2 monomers and binding was double that of controls.)

It is still thought that dopamine mesolimbic pathways may be hyperactive, resulting in hyperstimulation of D2 receptors and positive symptoms. There is also growing evidence that, conversely, mesocortical pathway dopamine projections to the prefrontal cortex might be hypoactive (underactive), resulting in hypostimulation of D1 receptors, which may be related to negative symptoms and cognitive impairment. The overactivity and underactivity in these different regions may be linked, and may not be due to a primary dysfunction of dopamine systems but to more general neurodevelopmental issues that precede them. Increased dopamine sensitivity may be a common final pathway.

Another reliable finding, repeatedly found, is that there is a some sixfold excess of binding sites insensitive to a certain testing agent (raclopride) Dr Seeman later said this increase was probably due to the increase in d2 monomers. Such an increase in monomers, occurs via the cooperativity mechanism which is responsible for d2high and d2low, the supersensitive and lowsensitivity states of the d2 dopamine receptor. More specifically, "an increase in monomers, may be one basis for dopamine supersensitivity."

Another one of Philip Seeman's findings was that the dopamine D2 receptor protein looked abnormal in schizophrenia. Proteins change states by flexing. The activating of the protein by folding could be permanent or fluctuating, just like the courses of patients' illnesses waxes and wanes. Increased folding of a protein leads to increased risk of 'additional fragments' forming The schizophrenic d2 receptor has a unique additional fragment when digested by papain in the test-tube, but none of the controls exhibited the same fragment. The D2 receptor in schizophrenia are thus in a highly active state as found by Philip Seeman et al.

Glutamate

Main article: Glutamate hypothesis of schizophrenia

Interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in schizophrenia. This has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that the glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition. The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Further support of this theory has come from preliminary trials suggesting the efficacy of coagonists at the NMDA receptor complex in reducing some of the positive symptoms of schizophrenia.

Other

Dyregulation of neural calcium homeostasis has been hypothesized to be a link between the glutamate and dopaminergic abnormalities and some small studies have indicated that calcium channel blocking agents can lead to improvements on some measures in schizophrenia with tardive dyskinesia.

There is evidence of irregular cellular metabolism and oxidative stress in the prefrontal cortex in schizophrenia, involving increased glucose demand and/or cellular hypoxia.

Mutations in the gene for brain-derived neurotrophic factor (BDNF) have been reported to be a risk factor for the disease.

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  54. Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18408624, please use {{cite journal}} with |pmid=18408624 instead.