BACKGROUNDWe investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway.METHODWe measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, cAMP, and ATF-2 proteins.RESULTSWe found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications.CONCLUSIONTaken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia.

Fluorine-19 NMR spectra were acquired from extracts of tissues from heads of rats given the antipsychotic drug trifluoperazine (TFP). Contributions to the in vivo 19F spectra from tissues other than brain were negligible. The in vivo 19F resonance at -62.3 ppm from CCl3F consisted of 6–8 resolved resonances in vitro. Some in vitro resonances were assigned to previously identified TFP metabolites. Multiple resonances in vitro partially explain the relatively large line width seen in vivo for TFP. Unidentified metabolites were observed at about -74 to -75 ppm in a number of spectra of extracts of brain and muscle. Magn Reson Med 43:756–759, 2000. © 2000 Wiley-Liss, Inc.

The P1 midlatency auditory evoked potential was studied in female rape victims with Posttraumatic Stress Disorder (PTSD) and compared to an age-matched female control group; and in male combat veterans with PTSD and compared to three groups of age-matched male control subjects. Sensory gating of the P1 potential was determined using a paired click stimulus paradigm in which the stimuli were presented at 250, 500 and 1000 msec interstimulus intervals (ISI). Results showed that sensory gating of the P1 potential was significantly decreased at the 250 msec ISI, and that there was a numerical, but not a statistically significant, decrease in sensory gating at the other intervals tested in both male and female PTSD subjects compared to all control groups. Since the P1 potential may be generated, at least in part, by the reticular activating system, dysregulation of sensory processing by elements of this system may be present in PTSD.

An impairment of prefrontal cortical functioning in schizophrenia ('hypofrontality') has been suggested by clinical, neuroimaging, and postmortem brain tissue studies. We used Western immunoblot and Northern hybridization analyses of postmortem brain tissue obtained from 14 schizophrenic patients and 12 control patients of similar ages to measure tissue levels of synaptophysin (a structural synaptic vesicle protein) and of SNAP-25 (a 25-kDa presynaptic protein), and their encoding mRNAs, in Brodmann's area 10 of prefrontal cortex. There were significant decreases in tissue levels of both of these proteins in prefrontal cortex of schizophrenic patients relative to controls. In contrast, tissue levels for the mRNAs encoding these proteins were not decreased in schizophrenic patients. Subsequent labeling of the same Western immunoblots showed no difference in tissue levels of glial fibrillary acidic protein (GFAP) in schizophrenic and control patients. Similarly, subsequent hybridization of the same Northern hybridization membranes showed no difference in tissue levels of GFAP mRNA or of 28S rRNA in schizophrenic and control patients. These alterations in tissue levels of synaptophysin and SNAP-25 are consistent with the idea that the clinically observed 'hypofrontality' of schizophrenia arises from abnormalities of synaptic number or structural integrity in prefrontal cortex.

Localized, in vivo 1H magnetic resonance spectroscopy has been performed in a number of brain regions of neuropsychiatric interest in male and female control subjects to determine if gender and region affect the measured metabolite ratios. In contrast to some previous reports, no significant differences were seen in any region for any metabolite ratio between males and females. As expected, significant variations with brain region were seen for metabolite ratios for the total group of subjects.

Background: Mitogen-activated protein kinases (MAPKs) are important mediators of signal transduction from the cell surface to the nucleus and have been implicated in the integration of a variety of physiologic processes in most cells, including neurons. To investigate the possible involvement of MAPKs in schizophrenia, we compared the levels of the MAPK intermediates in postmortem brain tissue obtained from schizophrenic and control subjects. Our focus was on the cerebellar vermis because of evidence suggesting that schizophrenia is associated with abnormalities of structure, function, and signal transduction in this brain region.Methods: Cytosolic proteins were fractionated by gel electrophoresis and subjected to Western blot analysis using polyclonal MAPK antibody, which detects total extracellular signal-regulated kinases (ERKs) 1 and 2 levels, and monoclonal MAP kinase phosphatase (MKP) 2 antibody.Results: Schizophrenic subjects had increased levels of ERK2 [2763 +/- (SD) 203 vs. 2286 +/- 607 arbitrary units, U = 17, p < .05] in cerebellar vermis. The levels of a dual specificity tyrosine phosphatase, MKP2, were significantly decreased in cerebellar vermis (1716 +/- 465 versus 2372 +/- 429 arbitrary units, U = 12, p < .02) from schizophrenic patients. ERK1/MKP2 and ERK2/2MKP2 ratios in cerebellar vermis, but not in other brain regions, were significantly different in schizophrenic subjects as compared to control subjects (U = 15, p less than or equal to .027; U = 3, p < .001, respectively).Conclusions: MAPK levels are elevated in the cerebellar vermis of schizophrenic subjects. This could result from a protein dephosphorylation defect in vivo and might be involved in the pathology of the disease. Biol Psychiatry 1999;46:689-696 (C) 1999 Society of Biological Psychiatry.

Recent findings using volumetric MRI techniques have revealed that patients with combat‐related and noncombat‐re‐lated posttraumatic stress disorder (PTSD) have reductions in right hippocampal volume. Twenty‐one veterans with PTSD and eight age‐matched control veterans were studied using proton magnetic resonance spectroscopy to test the hypothesis that the N‐acetyl‐L‐aspartic acidkreatine (NAAICr) ratio would be decreased in the right medial temporal lobe structures of patients with PTSD compared to controls. Patients with PTSD displayed significantly lower NAA/Cr ratio for the right medial temporal lobe relative to the left (P ⩽ 0.011). Patients with PTSD also had lower NNCr in right medial temporal lobe (P ⩽ O.013) and lower choline/Cr in left medial temporal lobe (P ⩽ 0.030) compared to control subjects. Because NAA is regarded as an indicator of neuronal density, this finding suggests that the neuronal density of right‐sided medial temporal structures in patients with combat‐related PTSD may be decreased.

Schizophrenia is a disorder with an unclear pathophysiology, despite numerous attempts to elucidate its etiology. We have employed proton magnetic resonance spectroscopy in vivo to explore the neurochemistry of several brain regions (left frontal and temporal cortices, left basal ganglia, and left and right thalamus) in patients with schizophrenia and in normal control subjects. We have also examined patients in different medication states. A trend toward a decreased level of inositol/creatine was found in the left temporal lobe of patients with schizophrenia, as was a trend toward a reduced level of N-acetylaspartate/creatine in the left thalamus of patients. In schizophrenic patients treated with atypical antipsychotics, decreased levels of choline were found in the left basal ganglia, while increased levels of N-acetylaspartate were found in the left frontal cortex. These results suggest altered metabolism in patients with schizophrenia, and imply that further study is needed to clarify the effects of the more recently available antipsychotics.

Background: Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine(2) (5-HT2) receptors than for D-2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d).Methods: In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (less than or equal to 750 mg/d), n = 96; low-dose quetiapine fumarate (less than or equal to 250 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using chi(2) tests.Results: Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P < .001, BPRS; P = .003, Clinical Global Impression Severity of Illness item; and P = .003, BPRS positive-symptom cluster) differences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative symptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustained elevations of prolactin, or clinically significant changes in hematologic parameters.Conclusions: Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.

5-HT2 receptors in all schizophrenics regardless of their neuroleptic treatment history. In other areas examined 5-HT2 receptor density was decreased in neuroleptic treated schizophrenic patients, while those off drugs showed no alterations. We found no significant differences between control and schizophrenic subjects in the density of 5-HT uptake sites measured with two ligands, [3H]cyanoimipramine and [1251]RTI-55, nor did we find significant differences in the density of serotonin terminals measured by immunoautoradiography.

Some evidence suggests that thalamic dysfunction could explain some of the signs and symptoms of schizophrenia. We measured the absolute concentrations of amino acid metabolites in thalamus, frontal pole, and cerebellar ver-mis in extracts of postmortem brains from 8 schizophrenics and 10 controls using high-resolution H-1-magnetic resonance spectroscopy, The concentrations of N-acetyl aspartate, glutamate, and valine tended to be reduced in the thalamus of the schizophrenic group. Although it is difficult to ascribe significance to the ''tendencies,'' these data may tend to support other data suggesting decreased thalamic volume or neuronal number in schizophrenia. (C) 1997 Society of Biological Psychiatry.

The objective was to replicate a reported decrease of choline acetyltransferase (ChAT) in the mesopontine tegmentum of deceased schizophrenics and to see if such a decrease is related to their cognitive status as measured during life. Rigorous antemortem psychiatric evaluations were performed on our large population of schizophrenic patients. Mesopontine tissue was collected promptly following death from eight of these patients, from an additional five schizophrenics without systematic premortem psychiatric evaluation, and from control subjects. ChAT content of this brain tissue was determined using Western immunoblot analysis. There were 13 schizophrenic patients and 8 control subjects. The mean age of subjects in the two groups was similar (64 +/- 9 yr vs 63 +/- 10 yr). Even in the face of reduced post mortem intervals in the patients with schizophrenia, mesopontine tegmental ChAT concentrations were depressed by 70% in schizophrenic patients (1.28 +/- 1.74 vs 4.39 +/- 3.20 ng ChAT/micrograms tissue protein, P < 0.01), and correlated with orientation and reasoning (rs = 0.90 and 0.98, respectively) in those subjects assessed antemortem. Mesopontine ChAT concentrations are depressed in schizophrenia and correlate significantly with measures of cognitive performance in patients with this disorder.

A high proportion of neurons in the cerebellum and in cholinergic brainstem nuclei stain positive for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPHd), which is a nitric oxide synthase (NOS). Recent evidence suggests that schizophrenia may involve increased numbers of NADPHd-stained neurons in different areas of the subcortex. This led us to examine the actual concentration of NOS in postmortem brain specimens of cerebellum, and the relevant regions of brainstem tegmentum, to see if NOS concentrations were also increased in schizophrenia. Postmortem brain tissue was obtained at autopsy from schizophrenics and controls who did not have other brain disease. In patients with schizophrenia, NOS concentration was higher.