Mechanisms of schizophrenia

Artistic view of what the world feels like with schizophrenia

The underlying mechanisms of schizophrenia, a mental disorder characterized by a disintegration of the processes of thinking and of emotional responsiveness, are complex. A number of theories attempt to explain the link between altered brain function and schizophrenia,[1] the most important of which are the dopamine hypothesis and the glutamate hypothesis. Note that these theories are separate from the causes of schizophrenia, which deal with actual starting points of the illness instead, e.g. genetic and environmental factors. The current theories attempt to explain how changes in brain functioning can contribute to symptoms of the disease.

Pathophysiology

The exact pathophysiology of schizophrenia remains poorly understood.[2] Since the coining of schizophrenia by Eugene Bleuler in 1908, quite a variety of theories have been proposed concerning its underlying pathophysiology. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis.[3][4][5] More recent theories evolve around specific dysfunction of interneurons, abnormalities in the immune system, and oxidative stress.[6][7][8][9][10][11]

Dopamine dysfunction

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", proposes that a malfunction involving dopamine pathways is therefore the cause of (the positive symptoms of) schizophrenia. It is also supported by the fact that amphetamines, which trigger the release of dopamine, may exacerbate the psychotic symptoms in schizophrenia.[12]

This influential theory proposed that excess activation of D2 receptors is the cause of (the positive symptoms of) schizophrenia. Although postulated for about 20 years based on the D2 blockade effect common to all antipsychotics, it was not until the mid-1990s that PET and SPET imaging studies provided supporting evidence. This explanation is now thought to be simplistic, partly because newer antipsychotic medication (called atypical antipsychotic medication) can be equally effective as older medication (called typical antipsychotic medication), but also affects serotonin function and may have slightly less of a dopamine blocking effect.[13]

Evidence for this theory includes[14] findings that the potency of many antipsychotics is correlated with their affinity to dopamine D2 receptors;[15] and the exacerbatory effects of a dopamine agonist (amphetamine) and a dopamine beta hydroxylase inhibitor (disulfiram) on schizophrenia;[16][17] and post-mortem studies initially suggested increased density of dopamine D2 receptors in the striatum. Such high levels of D2 receptors intensify brain signals and can exacerbate positive symptoms (i.e. hallucinations and paranoia) in schizophrenia. Impaired glutamate (a neurotransmitter which directs neuron to pass along an impulse) activity appears to be another source of schizophrenia symptoms.[18]

However, there was controversy and conflicting findings over whether postmortem findings resulted from drug tolerance to 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[19] A recent review of imaging studies in schizophrenia shows confidence in the techniques, while discussing such operator error.[20] 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." [21]

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.[22][23] While the review by Laruelle acknowledged more sites were found using methylspiperone, it discussed the theoretical reasons behind such an increase (including the monomer-dimer equilibrium) and called for more work to be done to 'characterise' the differences. 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.[24]

Giving a more precise explanation of this discrepancy in D2 receptor has been attempted by a significant minority. Radioligand imaging measurements involve the monomer and dimer ratio, and the 'cooperativity' model.[25] Cooperativitiy is a chemical function in the study of enzymes.[26] Dopamine receptors interact with their own kind, or other receptors to form higher order receptors such as dimers, via the mechanism of cooperativity.[27] Philip Seeman has said: "In schizophrenia, therefore, the density of [11C] methylspiperone sites rises, reflecting an increase in monomers, while the density of [11C] raclopride sites remains the same, indicating that the total population of D2 monomers and dimers does not change."[28] (In another place Seeman has said methylspiperone possibly binds with dimers[29]) With this difference in measurement technique in mind, the above-mentioned meta-analysis uses results from 10 different ligands.[30] Exaggerated ligand binding results such as SDZ GLC 756 (as used in the figure) were explained by reference to this monomer-dimer equilibrium.

According to Seeman, "...Numerous postmortem studies have consistently revealed D2 receptors to be elevated in the striata of patients with schizophrenia".[31] 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.[32] 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).[33][34] 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.[35]

Some animal models of psychosis are similar to those for addiction – displaying increased locomotor activity.[36] 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.[37]

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." [38] (The experiment used 3-N-[11C]methylspiperone – the same as mentioned by 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.[39] Increased dopamine sensitivity may be a common final pathway.[25]

Another finding is a six-fold excess of binding sites insensitive to the testing agent, raclopride;[40][41] Seeman said this increase was probably due to the increase in D2 monomers.[28] Such an increase in monomers may occur via the cooperativity mechanism[42] which is responsible for D2High and D2Low, the supersensitive and lowsensitivity states of the D2 dopamine receptor.[43] More specifically, "an increase in monomers, may be one basis for dopamine supersensitivity".[44]

The importance of the dopamine theory has been further strengthened by the finding for common variant in the dopamine D2 receptor as candidate loci for the disease, as identified by the large genome-wide association study which included over 35.000 cases and over 110.000 controls.[45]

Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. Some studies have suggested that disruption of the auditory thalamocortical projections give rise to hallucinations,[46] while dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions.[47]

Glutamate

Beside the dopamine hypothesis, interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of schizophrenia. This has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia[48] and the discovery that the glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition.[49]

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.[50] Positive symptoms fail however to respond to glutamatergic medication.[51] A commonly known side effect associated with schizo-affective patients known as akathisia (mistaken for schizophrenic symptoms) was found to be associated with increased levels of norepinephrine.[52]

Reduced mRNA and protein expression of several NMDA receptor subunits has also been reported in postmortem brains from patients with schizophrenia.[53]

Kynurenic acid

For the last decade increased attention has been focused on a product produced in the metabolism of the essential amino acid tryptophan in the Kynurenine pathway called kynurenic acid (KYNA). KYNA is produced from kynurenine by kynurenine aminotransferase I and II and increased levels have been observed in cerebrospinal fluid of schizophrenic patients as well as in post-mortem brains of schziphrenic patients.[54][55] KYNA has been seen to function as a NMDA receptor antagonist[56] which could explain the decreased glutamate activity seen in schizophrenic patients and goes in hand with the glutamate hypothesis of schizophrenia where NMDA receptor antagonists have been shown to induce negative symptoms of schizophrenia. Elevated levels of KYNA has also been shown to increase dopaminergic activity in midbrain[55] which in turn goes in hand with the dopamine hypothesis of schizophrenia and could explain the positive symptoms in schizophrenia. It has also been found that the mRNA levels and activity of Kynurenine 3-monooxygenase, an enzyme further down in the Kynurenine pathway, are lowered in the prefrontal cortex of schizophrenic patients[57] causing increased levels of KYNA and suggests that there might be a genetic factor involved. Beyond genetic influence, increased KYNA has also been linked to increased levels of Interleukin-1 suggesting an inflammatory component may be involved in the onset and progression of schizophrenia.[58]

Interneuron dysfunction

A more novel hypothesis concerning the pathophysiology of schizophrenia, one that closely relates to the glutamate hypothesis, is one that evolves around dysfunction of interneurons in the brain.[6][7][8] Interneurons in the brain are GABAergic, and function mainly through the inhibition of other cells.

Several studies have identified a decrease in GAD67 mRNA and protein in postmortem brains from patients diagnosed with schizophrenia as compared to controls.[59] Interestingly, these reductions were found in only a subset of cortical interneurons. Furthermore, GAD67 mRNA was completely undetectable in a subset of interneurons also expressing the calcium-binding protein parvalbumin. Levels of parvalbumin protein and mRNA were also found to be lower in patient brains in various regions in the brain. Actual numbers of parvalbumin interneurons have been found to be unchanged in these studies, however, except for a single study showing a decrease in parvalbumin interneurons in the hippocampus.[60] Together, this suggests that parvalbumin interneurons are somehow specifically affected in the disease.

Several studies have tried to assess levels in GABA in vivo in the patients with schizophrenia, but these findings have remained inconclusive.

ErbB4 protein abnormalities are also associated with neuropathophysiology of the schizophrenic brain.[61]

The largest meta-analysis on copy-number variations (CNVs), structural abnormalities in the form of tiny deletions or duplications, to date for schizophenia, published in 2015, was the first genetic evidence for the broad involvement of GABAergic neurotransmission.[62]

Immune system abnormalities

In more recent year a novel hypothesis of schizophrenia was formulated, one of inflammation and immune system abnormalities.[11] Abnormal immune system development may help explain roles of environmental effect such as prenatal hazards, post-pubertal onset, stress, climate, and infections, in addition to genetic effects.[63] The immune hypotheses is supported by findings of high levels of immune markers in the blood of schizophrenia patients.[64] High levels of immune markers have also been associated with having more severe psychotic symptoms.[65][66] Furthermore, in 2011, a meta-analysis of genome-wide association studies discovered that 129 out of 136 single-nucleotide polymorphisms (SNP) significantly associated with schizophrenia were located in the major histocompatibility complex region of the genome.[67]

Oxidative stress

A theory that has gained more support in recent years is that a large role is played in the disease by oxidative stress.[10][68] Redox dysregulation in early development can potentially influence development of different cell types that have been shown to be impaired in the disease.

Although yet unclear how exactly oxidative stress in schizophrenia would arise, oxidative stress has been shown to affect maturation of oligodendrocytes,[69] which are the myelinating cell types in the brain, possible underlying the white matter abnormalities found in the brain (see below).

Furthermore, oxidative stress could also influence the development of GABAergic interneurons,[70] which have also been found to be dysregulated in schizophrenia.

Structural abnormalities

Beside theories concerning the functional mechanism underlying the disease, quite some structural findings have been identified as well using a wide range of imaging techniques. 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.[71]

MRI

There have also been findings of differences in the size and structure of certain brain areas in schizophrenia. A 2006 meta-analysis of MRI studies found that whole brain and hippocampal volume are reduced and that ventricular volume is increased in patients with a first psychotic episode relative to healthy controls. The average volumetric changes in these studies are however close to the limit of detection by MRI methods, so it remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.[2] In first episode psychosis typical antipsychotics like haloperidol were associated with significant reductions in gray matter volume, whereas atypical antipsychotics like olanzapine were not.[72] Studies in non-human primates found gray and white matter reductions for both typical and atypical antipsychotics.[73]

Abnormal findings in the prefrontal cortex, temporal cortex and anterior cingulate cortex are found before the first onset of schizophrenia symptoms. These regions are the regions of structural deficits found in schizophrenia and first-episode patients.[74] Positive symptoms, such as thoughts of being persecuted, were found to be related to the medial prefrontal cortex, amygdala, and hippocampus region. Negative symptoms were found to be related to the ventrolateral prefrontal cortex and ventral striatum.[74]

Ventricular and third ventricle enlargement, abnormal functioning of the amygdala, hippocampus, parahippocampal gyrus, neocortical temporal lobe regions, frontal lobe, prefontal gray matter, orbitofrontal areas, parietal lobs abnormalities and subcortical abnormalities including the cavum septi pellucidi, basal ganglia, corpus callosum, thalamus and cerebellar abnormalities. Such abnormalities usually present in the form of loss of volume.[75]

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.[76] However, at variance with some findings in individuals with chronic schizophrenia significant group differences of temporal lobe and amygdala volumes are not shown in first-episode patients on average.[77]

Finally, MRI studies utilizing modern cortical surface reconstruction techniques have shown widespread reduction in cerebral cortical thickness (i.e., "cortical thinning") in frontal and temporal regions[78][79] and somewhat less widespread cortical thinning in occipital and parietal regions[79] in patients with schizophrenia, relative to healthy control subjects. Moreover, one study decomposed cortical volume into its constituent parts, cortical surface area and cortical thickness, and reported widespread cortical volume reduction in schizophrenia, mainly driven by cortical thinning, but also reduced cortical surface area in smaller frontal, temporal, parietal and occipital cortical regions.[80]

The largest combined neuroimaging study with over 2000 patients and 2500 controls has replicated these previous findings.[81] Here, the authors found volume increases in the lateral ventricles (+18%), caudate and pallidum, and extensive decreases in the hippocampus (-4%), thalamus, amygdala and nucleus accumbens. Together, this indicates that extensive changes occur in vivo in brains in patients suffering from schizophrenia.

DTI

Diffusion tensor imaging (DTI) allows for the investigation of white matter more closely than traditional MRI.[75] Over 300 DTI imaging studies have been published examining white matter abnormalities in schizophrenia.[82][83] Although quite some variation has been found pertaining to the specific regions affected, the general consensus states a reduced fractional anisotropy in brains from patients with schizophrenia versus controls. Importantly, these differences between patients and controls could potentially be attributed to lifestyle effects, medication effects etc. Therefore, more recently several studies have been perform in first-onset schizophrenia patients that have never recent any medication, so-called medication-naive subjects. These studies, although still few in number, also found reduced fractional anisotropy in patient brains compared to control brains. As with earlier findings, abnormalities can be found throughout the brain, although the corpus callous seemed to be most commonly effected. Together, this indicates that abnormalities in white matter could potentially be at the core of the schizophrenia pathophysiology.

CT

Computed Tomography scans of schizophrenic brains show several pathologies. The brain ventricles are enlarged as compared to normal brains. The ventricles hold cerebrospinal fluid (CSF) and enlarged ventricles indicate a loss of brain volume. Additionally, schizophrenic brains have widened sulci as compared to normal brains, also with increased CSF volumes and reduced brain volume.[75][84]

Functional abnormalities

PET

Data from a PET study[85] suggests that the less the frontal lobes are activated (red) during a working memory task, the greater the increase in abnormal dopamine activity in the striatum (green), thought to be related to the neurocognitive deficits in schizophrenia.

PET scanning is a useful tool to allow the imaging of brain physiology.[86] PET is useful to elaborate hypothesis of the origins of brain pathology, to relate symptoms to biological variables and to study individuals at increased risk. Studies measuring cerebral metabolic rate for glucose (CMRglc) and cerebral blood flow (CBF) have indicated an indirect measurement of synaptic activity. The ability to detect dysfunction of the communication between glutamatergic neurons and astrocytes may lead to an increased understanding of altered functional brain images.[87]

PET scan findings indicate cerebral blood flow decreases in the left parahippocampal region. PET scans also show a reduced ability to metabolize glucose in the thalamus and frontal cortex. PET scans also show involvement of the medial part of the left temporal lobe and the limbic and frontal systems as suffering from developmental abnormality. PET scans show thought disorders stem from increased flow in the frontal and temporal regions while delusions and hallucinations were associated with reduced flow in the cingulate, left frontal, and temporal areas. PET scans done on patient who were actively having auditory hallucinations revealed increased blood flow in both thalami, left hippocampus, right striatum, parahippocampus, orbitofrontal, and cingulate areas.[75]

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