Axonal myelin decrease in the splenium in major depressive disorder.

The corpus callosum has become a key area of interest for researchers in severe mental illness. Disruptions in fractional anisotropy in the callosum have been reported in schizophrenia and major depressive disorder. No change has been reported in oligodendrocyte density and overall size of the callosum in either illness, suggesting that gross morphology is unchanged, but subtler organisational disruption may exist within this structure. Using high-resolution oil immersion microscopy, we examined the cross-sectional area of the nerve fibre and the axonal myelin sheath; and using standard high-resolution light microscopy, we measured the density of myelinated axons. These measurements were made in the splenium of the corpus callosum. Measures were taken in the sagittal plane in the callosal splenium to contrast with the previous similar examination of the callosal genu. Cases of major depressive disorder had significantly decreased mean myelin cross-sectional area (p = 0.014) per axon in the splenium than in controls or schizophrenia groups. There was no significant change in the density of myelinated axons. The results suggest a clear decrease of myelin in the axons of the callosal splenium in MDD, although this type of neuropathological study is unable to clarify whether this is caused by changes during life or has a developmental origin. In contrast with increased myelin in the callosal genu, this result suggests a longitudinal change in callosal myelination in major depressive disorder not present in normal or schizophrenic brains.

Axonal myelin increase in the callosal genu in depression but not schizophrenia.

BACKGROUND: Abnormalities in the anterior inter-hemispheric connectivity have previously been implicated in major depressive disorder. Disruptions in fractional anisotropy in the callosum and fornix have been reported in schizophrenia and major depressive disorder. Oligodendrocyte density and overall size of the callosum and fornix show no alteration in either illness, suggesting that gross morphology is unchanged but more subtle organizational disruption may exist within these brain regions in mood and affective disorders. METHOD: Using high-resolution oil-immersion microscopy we examined the cross-sectional area of the nerve fibre and the axonal myelin sheath, and using standard high-resolution light microscopy we measured the density of myelinated axons. These measurements were made in the genu of the corpus callosum and the medial body of the fornix at its most dorsal point. Measures were taken in the sagittal plane in the callosal genu and in the coronal plane at the most dorsal part of the fornix body. RESULTS: Cases of major depressive disorder had significantly greater mean myelin cross-sectional area (p = 0.017) and myelin thickness (p = 0.004) per axon in the genu than in control or schizophrenia groups. There was no significant change in the density of myelinated axons, and no changes observed in the fornix. CONCLUSION: The results suggest a clear increase of myelin in the axons of the callosal genu in MDD, although this type of neuropathological study is unable to clarify whether this is caused by changes during life or has a developmental origin.

Neuropathological changes in the substantia nigra in schizophrenia but not depression.

Schizophrenia is a chronic, disabling neuropsychiatric disorder characterised by positive, negative and cognitive symptoms. The aetiology is not known, although genetic, imaging and pathological studies have implicated both neurodevelopmental and neurodegenerative processes. The substantia nigra is a basal ganglia nucleus responsible for the production of dopamine and projection of dopaminergic neurons to the striatum. The substantia nigra is implicated in schizophrenia as dopamine has been heavily implicated in the dopamine hypothesis of schizophrenia and the prevalent psychotic symptoms and the monoamine theory of depression, and is a target for the development of new therapies. Studies into the major dopamine delivery pathways in the brain will therefore provide a strong base in improving knowledge of these psychiatric disorders. This post-mortem study examines the cytoarchitecture of dopaminergic neurons of the substantia nigra in schizophrenia (n = 12) and depression (n = 13) compared to matched controls (n = 13). Measures of nucleolar volume, nuclear length and nuclear area were taken in patients with chronic schizophrenia and major depressive disorder against matched controls. Astrocyte density was decreased in schizophrenia compared to controls (p = 0.030), with no change in oligodendrocyte density observed. Significantly increased nuclear cross-sectional area (p = 0.017) and length (p = 0.021), and increased nucleolar volume (p = 0.037) in dopaminergic neurons were observed in schizophrenia patients compared with controls, suggesting nuclear pleomorphic changes. No changes were observed in depression cases compared to control group. These changes may reflect pathological alterations in gene expression, neuronal structure and function in schizophrenia.

Changes in cortical thickness in the frontal lobes in schizophrenia are a result of thinning of pyramidal cell layers.

Decreased cortical thickness and reduced activity as measured by fMRI in the grey matter of the subgenual cingulate cortex have been reported in schizophrenia and bipolar disorder, and cortical grey matter loss has been reliably reported in the frontal and temporal lobes in schizophrenia. The aim of this study was to examine the thickness of each of the six cortical layers in the subgenual cingulate cortex, five frontal lobe and four temporal lobe gyri. We examined two separate cohorts. Cohort 1 examines the subgenual cingulate cortex (SCC) in schizophrenia (n = 10), bipolar disorder (n = 15) and major depressive disorder (n = 20) against control subjects (n = 19). Cohort two examines frontal and temporal gyri in schizophrenia (n = 16), major depressive disorder (n = 6) against matched controls (n = 32). The cohorts were selected with identical clinical criteria, but underwent different tissue processing to contrast the effect of chemical treatment on tissue shrinkage. Measurements of layer I-VI thickness were taken from cresyl-violet- and haematoxylin-stained sections in cohort one and from cresyl-violet- and H&E-stained sections in cohort two. SCC cortical thickness decreased in male subjects with bipolar disorder (p = 0.048), and male schizophrenia cases showed a specific decrease in the absolute thickness of layer V (p = 0.003). Compared to controls, the relative thickness of layer V in the crown of the SCC decreased in schizophrenia (p < 0.001). A significant decrease in total cortical thickness was observed across the frontal lobe in schizophrenia (p < 0.0001), with specific pyramidal layer thinning in layers III (p = 0.0001) and V (p = 0.005). There was no effect of lateralization. No changes were noted in temporal lobe cortical thickness. This study demonstrates diminished pyramidal layer thickness resulting in decreased frontal lobe thickness in schizophrenia.

Neuropathological changes in the nucleus basalis in schizophrenia.

The nucleus basalis has not been examined in detail in severe mental illness. Several studies have demonstrated decreases in glia and glial markers in the cerebral cortex in schizophrenia, familial bipolar disorder and recurrent depression. Changes in neocortical neuron size and shape have also been reported. The nucleus basalis is a collection of large cholinergic neurons in the basal forebrain receiving information from the midbrain and limbic system, projecting to the cortex and involved with attention, learning and memory, and receives regulation from serotonergic inputs. Forty-one cases aged 41-60 years with schizophrenia or major depressive disorder with age-matched controls were collected. Formalin-fixed paraffin-embedded coronal nucleus basalis sections were histologically stained for oligodendrocyte identification with cresyl-haematoxylin counterstain, for neuroarchitecture with differentiated cresyl violet stain and astrocytes were detected by glial fibrillary acid protein immunohistochemistry. Cell density and neuroarchitecture were measured using Image Pro Plus. There were larger NB oval neuron soma in the combined schizophrenia and major depression disorder groups (p = 0.038), with no significant change between controls and schizophrenia and major depression disorder separately. There is a significant reduction in oligodendrocyte density (p = 0.038) in the nucleus basalis in schizophrenia. The ratio of gemistocytic to fibrillary astrocytes showed a greater proportion of the former in schizophrenia (18.1 %) and major depressive disorder (39.9 %) than in controls (7.9 %). These results suggest glial cell abnormalities in the nucleus basalis in schizophrenia possibly leading to cortical-limbic disturbance and subcortical dysfunction.

"Revealed" Depression and drug treatment for schizophrenia.

Symptoms of depression are common in patients who have been treated for schizophrenia. Various concepts have been proposed to explain the relationship between depression and schizophrenia. Data for schizophrenic patients in prospective studies and a comparison group of depressives show that depressive symptoms are more prevalent during the acute phase of the illness and they decrease (rather than increase) in severity with effective neuroleptic treatment.

The third biannual winter workshop on schizophrenia. Schladming, Austria, Jan 26-31, 1986.

The following general principles seem to summarize the emphasis that was evident from the several days of multiple presentations and discussions. The need exists to continue to develop improvements in the tools applicable to research in psychiatry, both clinical and biological "instruments" that are both sensitive and specific to the questions asked. New molecular genetic technology has already been used to explore genetic susceptibility hypotheses, as well as novel viral associations. Imaging of brain receptor kinetics in vivo is in progress. Improvements in structured clinical rating scales for quantifying changes in biologically important clusters of symptoms (eg, negative vs positive symptoms) or the defining of prodromal symptoms that lead to relapse are critical to progress in etiological and treatment research. A genetic factor or factors for schizophrenia exist, although whether a "familial" type defines only a subgroup of schizophrenia is controversial. The relative importance of genetic vs environmental variables, and whether there is genetic and environmental heterogeneity, continue to be debated. The most important epidemiological data, the seasonality of birth, and the controversial question of geographical variation in prevalence can be clues to the etiology of schizophrenia and are presently being clarified. The pursuit of new treatments and modifications of present conventional treatments to increase the percentage of patients recovering from psychotic illnesses or lead to more complete recovery states is always of prime importance. An emphasis on clarifying the dopamine hypothesis of schizophrenia with PET continues to be at the forefront of psychiatric research. A focus on patients in a first episode of schizophrenia can clarify major issues.(ABSTRACT TRUNCATED AT 250 WORDS)

Schizophrenia, genetic retrenchment, and epidemiologic renaissance. The Sixth Biennial Winter Workshop on Schizophrenia, Badgastein, Austria, January 26-February 1, 1992.

A distinctive feature of these workshops, in addition to those noted in the introductory overview, is the selection of a relatively isolated location for a 1-week period. This, together with a rich and varied program and an ethos of informality, encourages participants to discuss not only the work presented but also their unpublished work and their intuitions based on preliminary data and analyses. Such an interchange is of inestimable value to the schizophrenia research community. In scientific terms, a panel of concluding discussants (Drs Kendell, Torrey, and Waddington) were in some measure of agreement that genetics, particularly molecular genetics, appears to be experiencing a period of retrenchment, while epidemiology is experiencing something of a renaissance. Maternal influenza was a prominent theme, although the data were far from consistent. It was argued by Dr Wessely that risk for schizophrenia putatively attributable to maternal influenza might be 5% to 10% of all cases, indicating a modest effect. Eclectically, Dr Kendell believed the effect to be "real" but slight and fragile, it being sought against large aggregates that almost inevitably result in differing findings from differing countries or from different data bases within a given country. Gender differences were also among the more prominent themes, not just in an epidemiologic context but also in a variety of other studies. This points anew to disturbances in schizophrenia of factors that regulate, or are intimately associated with, sexual dimorphism in brain development. Abnormalities in cerebral asymmetry continue to pervade a variety of research findings and point further to neurodevelopmental anomalies.(ABSTRACT TRUNCATED AT 250 WORDS)

Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group.

BACKGROUND: Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2 (5-HT2) receptors than for D2 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 (< or = 750 mg/d), n = 96; low-dose quetiapine fumarate (< or = 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.

Metabolic effects of combination glipizide and human proinsulin treatment in NIDDM.

The effects of 3 mo of treatment with a combination of glipizide and human proinsulin were studied in a small group of closely monitored patients. The patients had non-insulin-dependent diabetes mellitus (NIDDM) and poor glucose regulation, despite maximal sulfonylurea therapy. This was a randomized double-blind placebo-controlled trial in which there were three treatment groups who received either 20 mg glipizide given 30 min before breakfast and dinner and human proinsulin given subcutaneously at bedtime (n = 5), glipizide and human proinsulin placebo (n = 5), or glipizide placebo and human proinsulin (n = 5). Glycemic regulation was assessed by measurements of 24-h plasma glucose profiles and glycosylated hemoglobin. Our observations demonstrate that the combination of glipizide plus human proinsulin was more effective than either agent alone in controlling overall glycemia in patients with NIDDM. The data support the concept of use of an agent during the day that has its major effects postprandially and another agent at bedtime that is relatively hepatospecific.

Pathway and hemispheric differences in the event-related potential (ERP) to monaural stimulation: a comparison of schizophrenic patients with normal controls.

Previous research has established the stability of the contralateral dominance effect of the auditory temporal N120 peak amplitude. The purpose of this experiment was to examine event-related potential (ERP) asymmetries in schizophrenia, with particular reference to this contralateral dominance phenomenon. Ten unmedicated schizophrenic patients and ten controls heard a series of monaural tones, with no task requirements, while EEG was recorded from Cz, Pz, T3, and T4 referred to linked earlobes. Patients were characterized by smaller N120 amplitudes than controls, an effect that was slightly more pronounced at temporal sites. Patients failed to show the normal N120 contralateral dominance effect. Hemisphere asymmetry ratios revealed that 50% of the patients showed ipsilateral dominance in the auditory pathways. Furthermore, the hemisphere asymmetries (whether ipsilaterally or contralaterally dominant) seen in patients were significantly greater than for controls. These data offer a new level of explanation for schizophrenic performance abnormalities in dichotic listening paradigms and an explanation for for the apparent dichotomy in patient performance between exaggerated right ear advantage (REA) and left ear advantage (LEA).

The platelet polyphosphoinositide system in schizophrenia: the effects of neuroleptic treatment.

Signal transduction, mediated by the thrombin-stimulated polyphoshoinositide (PPI) turnover was studied in platelets from 44 schizophrenic patients and 33 healthy volunteers. The stimulated generation of inositol phosphates in the schizophrenic group was significantly greater than that in the control group. There was a lack of correlation between this augmented response and a variety of clinical parameters. The response in 9 drug-naive schizophrenic patients was not significantly different from that in controls. The response was significantly augmented in patients receiving neuroleptic treatment and in patients who had been off neuroleptics for at least 4 months. These results indicate that neuroleptic treatment may produce a long-term modification of signal transduction via the PPI system. Further studies are required to elucidate the exact nature of this modification and to explore the possibility that this effect of the neuroleptics may provide a novel approach to understanding the neurochemistry of schizophrenia and to monitoring the neuroleptic treatment.

Increased CSF amino acids and ventricular enlargement in schizophrenia: a preliminary study.

We found significantly higher levels of cerebrospinal fluid alanine, glycine, leucine, and phenylalanine in schizophrenic patients compared to healthy controls. Ventricular enlargement was present in 4 of 11 schizophrenics, and elevated CSF alanine was highly correlated with ventricular enlargement. The implications of these findings are discussed.

The effects of some polyamines on putative behavioural indices of mesolimbic versus striatal dopaminergic function.

The presence of polyamines in the brain, together with the previous reports of a structural similarity with neuroleptics, has led to the hypothesis that polyamines may have a modulatory role in the control of cerebral dopamine function. In this study, the effects of two polyamines, spermine and spermidine, were therefore tested on indices of dopamine-mediated behaviour in rats and mice. Spermine and spermidine caused a dose-dependent inhibition of mouse spontaneous climbing behaviour and wheel running at doses between 5 and 40 mg/kg IP but failed to cause catalepsy in the rat or to antagonise the stereotyped behaviour induced by apomorphine. When polyamines were given by intracerebral injection a similar regional selectivity was seen. Both spermine and spermidine (5-20 micrograms) when given bilaterally into the nucleus accumbens inhibited the hyperactivity caused by amphetamine injected into the same nucleus. However, when injected into the rat corpus striatum, neither polyamine was able to initiate any asymmetry or circling either spontaneously or after apomorphine injection IP. These results indicated a selective action of polyamines on mesolimbic dopamine behaviour. Possible implications for the understanding of psychosis and future work are suggested.

Role of polyamines in the membrane pathology of schizophrenia. A study using fibroblasts from schizophrenic patients and normal controls.

The polyamines putrescine, spermine, and spermidine play a major role in the regulation of cell growth and differentiation, metabolic pathways, and on cell membrane functions in mammalian systems. It has recently been suggested that polyamines may be involved in the pathophysiology of schizophrenia. Moreover, several reports suggest that schizophrenia may be associated with a generalized cell membrane abnormality. In view of these findings, we measured polyamine levels in cultured skin fibroblasts from schizophrenic patients and normal control subjects. These was a significant increase in the levels of spermidine and in total polyamines in fibroblasts and spermine in the culture medium from schizophrenic patients. This preliminary report suggests that polyamines may play an important role in the membrane abnormalities that have been reported in schizophrenic patients.

Elevated platelet phosphatidylinositol bisphosphate in mediated schizophrenics.

Levels of phosphatidyl inositol 4,5-bisphosphate (PIP2) have been measured in platelets from schizophrenic and healthy subjects by means of an immunoassay. Resting platelets from schizophrenic patients contained a significantly increased amount of PIP2 compared to controls. The agonist-stimulated hydrolysis of PIP2 in platelets from the schizophrenic group was also significantly greater than that in platelets from the control group. PIP2 plays an important role in cell signalling, and the observed abnormality may be reflected by an impairment in signal transduction via the inositol phospholipid pathway.

Symptom dimensions in old-age schizophrenics. Relationship to neuropsychological and motor abnormalities.

In most factor analytical studies of schizophrenic symptomatology, a three-factor solution was found. The aim of this study was to investigate symptomatological dimensions in old age and to clarify whether the dimensions correlate differently with neuropsychological and motor parameters. One hundred and thirty-one DSM-III-R chronic schizophrenics (mean age 68 years) were assessed using SANS, SAPS, a neuropsychological test battery and motor scales. Exploratory and confirmatory factor analyses yielded a model with three dimensions (negative, disorganized, paranoid), two of which (negative, disorganized) showed different correlations with neuropsychological and motor phenomena. Thus, three symptomatological dimensions could also be demonstrated in a chronic, old-age schizophrenic sample. The pathophysiological significance of the different correlations with neuropsychological and motor parameters should be clarified in neuroimaging and neuropathological studies.

Depression in schizophrenia: recognition and management in the USA.

The recognition of depression as a distinct syndrome within schizophrenia is a relatively recent development. The International Survey of Depression in Schizophrenia was designed to evaluate current clinical practice and prescribing trends in the management of the depressive component of schizophrenia. A 48-item questionnaire, comprising fixed-response questions and questions stimulated by case scenarios, was distributed to 37513 psychiatrists in the USA. A total of 43484 psychiatrists in Canada, Australia and 21 European countries also received the questionnaire. A total of 1128 US psychiatrists responded. Analysis of the data revealed that US psychiatrists identify symptoms of depression in approximately one-third of patients with schizophrenia, and largely appreciate the magnitude of the resultant burden on patients and their families. Responses to questions regarding treatment approaches and case scenarios demonstrated that the level of adjunctive prescribing of antidepressants in the USA is often higher than in other regions. Levels of awareness of depression in patients with schizophrenia and recognition of the need for effective management appear to be high among US psychiatrists. However, more than a quarter of these specialists rarely or never prescribe adjunctive antidepressant medications. Disparities in treatment approaches varying from the existing scientific evidence base underscore the need for further investigation into ways of optimizing the management of this serious coexisting condition.

Dysphoric and depressive symptoms in chronic schizophrenia.

This study suggests that depressive symptoms are less common in severe, chronic, schizophrenic inpatients than would be predicted if these symptoms were manifestations of negative symptoms or drug-induced parkinsonism. The findings further suggest that depressive symptoms in such patients are independent phenomena which conform to a depressive syndrome. This depression does not represent a misidentification of the negative symptoms affective flattening and alogia, as measured by the SANS, or parkinsonism or akathisia. The study findings fail to support the view that long-term depot antipsychotic medication plays an important role in the genesis of depression and dysphoria in chronic schizophrenic patients. Depressive symptoms were found to occur as frequently, and dysphoria more frequently, in schizophrenic patients in the year after drug withdrawal compared with patients continuing on maintenance drug treatment for the same period.

Charcoal-induced lipid reduction in uremia.

Charcoal, in divided oral doses totalling 35 g/day, was administered to six patients with renal insufficiency (creatinine clearance of 0 to 45 ml/min). Significant (P less than 0.01) reductions in serum cholesterol and triglycerides were observed in the three most hyperlipidemic patients. Maximal decreases in charcoal responders, as compared with control values, were for cholesterol (43%, 23.4% and 40.4%) and for triglycerides (76%, 60.3% and 64.3%). None of the patients showed altered concentrations of BUN, serum creatinine, uric acid, or vitamin A. Because of its safety and the profundity of its hypolipidemic action, it is suggested that charcoal may find applicability in the management of azotemic diabetic and nephrotic hyperlipidemia.