Many abnormalities have been found in schizophrenia, many of which I don't have listed here.  Most are of scientific interest, but don't affect treatment.  Some like the lower nighttime output of melatonin suggests possible interventions.

Schizophrenia's Neurology 2003: Schizophrenia shows no overall loss in the number of neurones but reductions in the size of neurones. The primary disorder in schizophrenia is neurodevelopmental rather than neurodegenerative. Changes are reported in microtubule associated protein 2 (MAP2), growth associated protein-43 (GAP-43), post-synaptic density protein 95 (PSD 95), and reelin. Reelin is a large secreted matrix protein that is involved in neuronal migration, facilitating normal brain architecture during development, and brains of patients with schizophrenia show a 30-50% reduction in reelin protein especially in the prefrontal cerebral cortex and hippocampus. Mutations in the reelin gene are also associated with a type of lissencephaly with cerebellar. Translocation interrupts the coding sequence of DISC-1, leading to loss of the C-terminal 257 amino acids of the DISC-1 protein in some Finnish & European ancestries. In late embryonic life when the cerebral cortex develops. DISC-1 interacts with a variety of cytoskeletal proteins that are important in neurodevelopment. A cytoskeletal protein, NUDEL (NudE-like), which is one of the DISC-1 interactors, is associated with cortical development and linked to LIS-1 (the disease gene for a form of lissencephaly) as described above. The mutant form of DISC-1 in the Scottish family fails to bind NUDEL. Expression of mutant, but not wild type, DISC-1 in neuronal PC12 cells reduces neurite outgrowth. BMJ 2003;327:632-633 (20 September)

Auditory Sensory Gating Deficit in Schizophrenic L Hemisphere: Converging evidence from double click paradigm EEG, MEG, and neuropsychological measures points to left hemisphere dysfunction as strongly related to the well-established sensory gating deficit in schizophrenia. Lateralization of auditory sensory gating and neuropsychological dysfunction in schizophrenia. Thoma RJ, Hanlon FM, et al. Am J Psychiatry. 2003 Sep;160(9):1595-605

Cortical Folding Reduced in Schizophrenia: Reduced bilateral cortical folding relative to healthy comparison subjects. Such reductions were more pronounced in those with the disorganized subtype and showed an inverse correlation with negative symptoms and a positive correlation with positive symptoms. The paranoid subtype showed reduced cortical folding that was restricted to the left hemisphere. Study of 40 pt with 20 controls. U Sao Paulo. Reduced cortical folding in schizophrenia: an MRI morphometric study. Sallet PC, Elkis H, et al. Am J Psychiatry. 2003 Sep;160(9):1606-13

DARPP-32 Plays Role: DARPP-32 is a key regulatory protein, involved in controlling receptors, ion channels and other physiological factors and is activated and de-activated ultimately by neurotransmitters that are implicated in the development of schizophrenia. A reduction of DARPP-32 required for functions in the brain could contribute to the cognitive dysfunction seen in the disease. In the brains of 14 deceased people who had schizophrenia, DARPP-32 was found to be reduced significantly in the dorsolateral prefrontal cortex, which has consistently been associated with the symptoms of schizophrenia. The researchers found low levels of DARPP-32 in people who had schizophrenia, but normal levels in people who did not have the disease. DARPP-32 was not found to be reduced in another area of the brain also associated with schizophrenia.

DHEA Up Dramatically in Schizophrenics: Plasma DHEA were strongly elevated in 23 schizophrenic patients (91 nmol/l) compared to 23 controls (24 nmol/l) (p<0.0001). Plasma dehydroepiandrosterone levels are strongly increased in schizophrenia. Michele F, Caltagirone C, et al. University of Rome, Italy. J Psychiatr Res. 2005 May;39(3):267-73. Ed: This is a very small study, but an unexpected finding.

Folate Low In Interictal Psychosis: In a study of the interictal "schizophrenia-like" psychosis (interictal psychosis ) of epilepsy, researchers checked the plasma folate, vitamin B12, and homocysteine levels of 32 age- and sex-matched epileptic patients with or without interictal psychosis. The epileptic patients with interictal psychosis had significantly lower folate levels and higher homocysteine levels than those without interictal psychosis. Folate supplementation, in addition to antipsychotics, might play a beneficial role in the treatment of interictal psychosis in epileptic patients. Plasma folate and homocysteine levels may be related to interictal "schizophrenia-like" psychosis in patients with epilepsy. Monji A, Yanagimoto K, et al. Kyushu University, Japan. J Clin Psychopharmacol. 2005 Feb;25(1):3-5

GABAergic Interneuron with Parvalbulmin Deficit: selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis. U Sheffield. Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons. Reynolds GP, Beasley CL, Zhang ZJ. J Neural Transm 2002 May;109(5-6):881-9; Neuropathological studies have demonstrated deficits of GABAergic interneurons in the hippocampus in schizophrenia. and selective deficits in some GABAergic sub-populations defined by calcium-binding proteins (CBPs) have been reported in the cortex in schizophrenia. In the present study, the relative densities of cells immunoreactive for the CBPs parvalbumnin (PV) and calretinin (CR) were determined in hippocampal tissue sections taken from patients with schizophrenia, bipolar disorder and major depression and from matched control subjects (15 per group). No significant difference in the density of CR-immunoreactive neurons was found between subject groups. Relative to normal controls, schizophrenic patients showed a significant and profound deficit in the relative density of PV-immunoreactive neurons in all hippocampal sub-fields. These reductions were more apparent in male than female schizophrenic patients, and were unrelated to antipsychotic drug treatment, age or duration of illness. The density of PV-immunoreactive neurons did not differ significantly from controls in the depression group, although a trend toward decreased relative density of PV-immunoreactive neurons was apparent in bipolar disorder that reached significance in one sub-field. Schizophr Res 2002 May 1;55(1-2):1-10

Glial Loss a Role: In MDD, post-mortem reductions in glial cell density (30%; P = 0.007) in layer 5 and neuronal size (20%; P = 0.003) in layer 6. Also, glial cell density (34%; P = 0.003) was reduced in layer 5 in schizophrenia, while neuronal size was reduced in layers 5 (14%) (P = 0.006) and 6 (18%; P = 0.007) in BPD. The spatial pattern investigation of neurons and glia demonstrated no alteration in the clustering of glia about neurons. Cereb Cortex 2002 Apr;12(4):386-394

Glycogen synthase kinase-3 (GSK3) is an important enzyme that modulates many aspects of neuronal function. Aibnormal activity of GSK3 is present in mood disorders and schizophrenia, and GSK3 is a protein kinase target for psychotropics. Serotonin regulates GSK3 by acutely increasing its N-terminal serine phosphorylation. Regulation of phospho-Ser-GSK3 is a shared effect among several atypical antipsychotics, including olanzapine, clozapine, quetiapine, and ziprasidone.  Int J Neuropsychopharm 2006 May 4;:1-13.

Grey Matter Loss L-Sided: left-biased progressive volume reduction in the Heschl gyrus and planum temporale gray matter in patients with first-episode schizophrenia in contrast to patients with first-episode affective psychosis and control subjects. Schizophrenia but not affective psychosis seems to be characterized by a postonset progression of neocortical gray matter volume loss in the left superior temporal gyrus and thus may not be developmentally fixed. Progressive decrease of left Heschl gyrus and planum temporale gray matter volume in first-episode schizophrenia: a longitudinal magnetic resonance imaging study. Kasai K, Shenton ME, et al. Arch Gen Psychiatry. 2003 Aug;60(8):766-75

Grey Matter Progressive Loss: In first year after loss of grey matter. Calm Arch Gen Psych 11/02 59:1002

Homocysteine Elevated But Significance Unclear: Elevated plasma homocysteine is a risk factor for Alzheimer's disease as well as cerebral vascular disease. In measuring the homocysteine levels of 193 schizophrenic patients vs. 762 controls, the effect of schizophrenia was marked (p<0.0001) 16.3 muM vs. 10.6 muM in healthy controls. The increase was almost entirely in young male schizophrenic patients. In another study of homocysteine levels in 184 consecutively admitted schizophrenic patients and 305 control subjects, homocysteine levels were markedly increased in this population of newly admitted schizophrenic patients, especially in young males. However, no difference was found for CSF homocysteine levels between schizophrenia patients and controls. In an attempt to develop a model of homocysteine neurotoxicity, mice were fed homocysteine in water at a dose of 200 mg/kg/day. Homocysteine levels were elevated up to 800% at months 5 and 6, but no homocysteine-induced defects were found. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Levine J, et al. Ben Gurion University, Beersheva, Israel. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Aug 19

Internal Capsule Decreased Volume: Decreased volume found in the anterior limb of the internal capsule supports the hypothesis of abnormal frontothalamic connectivity in schizophrenia. Increased asymmetry of the internal capsule seems consistent with the notion of predominantly left-side pathology of schizophrenia. Toyama Univ. Decreased volume and increased asymmetry of the anterior limb of the internal capsule in patients with schizophrenia. Zhou SY, Suzuki M, et al. Biol Psychiatry. 2003 Aug 15;54(4):427-36

Kynurenic Acid, a Glutamate Receptor Antagonist, May Play a Role: Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in schizophrenia. In an analysis of KYNA in the cerebrospinal fluid (CSF) from 49 male healthy controls and 90 male patients with schizophrenia, patients had significantly higher levels of CSF KYNA (1.45 nM vs. 1.06 nM). CSF KYNA levels were significantly elevated both in drug-naive, first episode patients (1.53 nM, n=37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM, n=34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM, n=19). Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Nilsson LK, et al. Karolinska Institutet, Stockholm, Sweden. Schizophr Res. 2005 Aug 24

Melatonin: Night Time Melatonin Low: The 24-h profiles of plasma melatonin and cortisol were evaluated in 7 drug-free male paranoid schizophrenics and in 7 healthy controls. Compared with that of the normal controls, the circadian rhythm of plasma melatonin was absent in paranoid schizophrenics (p < 0.0001) whereas the 24-h profile of plasma cortisol was preserved, although at a slightly higher level (p < 0.0002). The melatonin/cortisol ratio was significantly higher in healthy subjects than in the schizophrenic patients. Depressed nocturnal plasma melatonin levels in drug-free paranoid schizophrenics. Monteleone P, et al. University of Naples, Italy. Schizophr Res. 1992 Apr;7(1):77-84; Similar: Neuro Endocrinol Lett. 2003 Jun-Aug;24(3-4):181-4; Neuro Endocrinol Lett. 2001 Apr;22(2):137-41; J Formos Med Assoc. 1998 Dec;97(12):830-7 and others.

Myelin: Possible Myelin Defect in Schizophrenia & M-D: Dmitri Tkachev, a neurobiologist at the Babraham Institute in Cambridge, England did autopsies of 15 schizophrenia, 15 manic depressives, and 15 controls. Lancet 9/6/03

NAAG Deficit Could Play a Role: The "glutamate hypothesis" of schizophrenia has emerged from the finding that phencyclidine (PCP) induces psychotic-like behaviors in rodents, possibly by blocking the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, thereby causing increased glutamate release. N-acetyl aspartylglutamate (NAAG), an endogenous peptide abundant in mammalian nervous systems, is localized in certain brain cells, including cortical and hippocampal pyramidal neurons. NAAG is synthesized from N-acetylaspartate (NAA) and glutamate, and NAA availability may limit the rate of NAAG synthesis. Although NAAG is known to have some neurotransmitter-like functions, NAA does not. NAAG is a highly selective agonist of the type 3 metabotropic glutamate receptor (mGluR3, a presynaptic autoreceptor) and can inhibit glutamate release. In addition, at low levels, NAAG is an NMDA receptor antagonist, and blocking of NMDA receptors may increase glutamate release. Taken together, low central NAAG levels may antagonize the effect of glutamate at NMDA receptors and decrease its agonistic effect on presynaptic mGluR3; both activities could increase glutamate release, similar to the increase demonstrated in the PCP model of schizophrenia. The central NAAG deficit, possibly through decreased synthesis or increased degradation of NAAG, may play a role in the pathogenesis of schizophrenia. There is evidence for this from magnetic resonance, postmortem, animal model, schizophrenia treatment, and genetic studies. The central NAAG deficit model of schizophrenia could explain the disease process, from the perspectives of both neurodevelopment and neurodegeneration, and may point to potential treatments for schizophrenia. Central N-acetyl aspartylglutamate deficit: a possible pathogenesis of schizophrenia. Tsai SJ. National Yang-Ming University, Taipei, Taiwan. Med Sci Monit. 2005 Sep;11(9):HY39-45

NMDA receptor Antag Similar to Schiz: N-methyl D aspartate glutamate receptor antagonist ketamine in DB PC study induced schiz like state after initial memory impairment. Newcomer, Wash U, Neuropsychopharm 2/99;20:106

Oligodendrocyte and Myelin Genes Much Less Active in Schiz and Bipolar: Robert Yolken, Johns Hopkins, Lancet 9/6/03 reports expression profiles of most known oligodendrocyte-specific and myelin-associated genes were greatly reduced, and several transcription factors known to coordinate myelin gene expression showed corresponding changes

Oligodendrocytes & White Matter Decreased: Study found a 27% decrease of both in schiz. severe pathology of oligodendrocytes in schizophrenia and provide a quantitative cellular correlate of the white matter changes observed by brain imaging in vivo, showing reduced fractional anisotropy in schizophrenia. The data support recent evidence that several genes encoding myelin-related proteins consistently exhibit reduced expression in schizophrenia. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Hof PR, Haroutunian V, Friedrich VL Jr, Byne W, Buitron C, Perl DP, Davis KL. Biol Psychiatry. 2003 Jun 15;53(12):1075-85. Similar findings on MRI and at autopsy. Mol Psychiatry. 2003 Sep;8(9):811-20

Oligodendrocytes Damaged: Glia cells 50% brain mass and 90% of cells and made up of astrocytes which support and repair and oligodendrocytes which make myelin. Dramatic damage to oligodendrocytes is present in the brains of patients with schizophrenia. Not only are oligodendrocyte counts in functionally important areas of the cortex significantly reduced, but electron microscope findings show that such areas exhibit abnormal inclusions between myelin sheath lamellae, showing evidence for cellular dysfunction. Anisotropy, a measure of the coherence of white matter, has also been shown to be reduced in frontal and temporal lobes of patients with schizophrenia. Oligodendrocytes also decreased in number and functioning. Davis KL. White-matter abnormalities in schizophrenia. American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Industry-supported Symposium No. 24D

Reelin mRNA Decreased in Hippocampus: Reelin mRNA was expressed by layer I neurons, interneurons, and interstitial white matter neurons. In subjects with schizophrenia, less reelin mRNA was expressed by interstitial white matter neurons in the hippocampal formation and by all three cell types in the prefrontal cortex. Reelin and synaptic protein expression correlated positively. CONCLUSIONS: Interstitial white matter neurons, presumed remnants of the cortical subplate, contribute to the reduction in reelin mRNA in schizophrenia. Down-regulation of reelin expression may in turn contribute to the synaptic pathology of the disorder. Am J Psychiatry 2006 Mar;163(3):540-2.

S100 Proteins Decreased in Schizophrenia: The S100 proteins are a family of calcium-binding proteins found in the central and peripheral nervous systems of vertebrates. S100beta, the most abundant member of this family in the CNS, mediates calcium signal transduction, and shows neurotrophic, gliotrophic and mitogenic actions that influence the development and maintenance of the nervous system. Another member of the S100 family (S100A10) was found to modulate phospholipid turnover by inhibiting the activity of enzyme phospholipase A2 (PLA2). In a study of S100beta protein in the plasma of 23 medicated schizophrenic patients and 23 healthy controls, it was reduced in patients (p=.003). S100beta protein accounts for 96% of the total S100 in the brain. The finding was not related to clinical variables or to intake of antipsychotic medication. Decreased S100beta could be related to the findings of increased PLA2 activity and to brain maldevelopment in schizophrenia. Decreased S100-beta protein in schizophrenia: preliminary evidence. Gattaz WF, Lara DR, et al. University Sao Paulo, Brazil. Schizophr Res. 2000 Jun 16;43(2-3):91-5.

Thomas E. Radecki, M.D., J.D.

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