Sex difference in cerebrospinal fluid/blood albumin quotients in patients with schizophreniform and affective psychosis.

BACKGROUND: The importance of cerebrospinal fluid (CSF) diagnostics for psychiatry is growing. The CSF/blood albumin quotient (QAlb) is considered to be a measure of the blood-CSF barrier function. Recently, systematically higher QAlb in males than in females was described in neurological patients. The aim of this study was to investigate whether a sex difference could also be detected in a well-characterized psychiatric cohort. METHODS: The patient cohort comprised 989 patients, including 545 females and 444 males with schizophreniform and affective syndromes who underwent CSF diagnostics, including QAlb measurement. The basic CSF findings and antineuronal autoantibody data of this cohort have already been published. This re-analysis employed analysis of covariance with age correction for QAlb mean values and chi2-testing for the number of increased age-corrected QAlb levels to investigate sex differences in QAlb. RESULTS: The QAlb levels were elevated above reference levels by 18% across all patients, and a comparison between male and female patients revealed a statistically significant sex difference, with increased values in 26% of male patients and a corresponding rate of only 10% in female patients (chi2 = 42.625, p < 0.001). The mean QAlb values were also significantly higher in males (6.52 ± 3.69 × 10-3) than in females (5.23 ± 2.56 × 10-3; F = 52.837, p < 0.001). DISCUSSION: The main finding of this study was a significantly higher QAlb level in male compared to female patients with psychiatric disorders, complementing previously described sex differences in neurological patient cohorts. This result indicates bias from some general factors associated with sex and could be partly explained by sex differences in body height, which is associated with spine length and thus a longer distance for CSF flow within the subarachnoid space down the spine from the occipital area to the lumbar puncture site in males compared to females. Hormonal influences caused by different estrogen levels and other sex-specific factors could also play a relevant role. The significance of the study is limited by its retrospective design, absence of a healthy control group, and unavailability of exact measures of spine length.

Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fluid and peripheral blood from patients with neurological and psychiatric disorders.

Recent studies suggest inflammatory mechanisms involved in the pathogenesis of major psychiatric disorders (MPD). T cells play a major role during inflammation, but little is known about T cell subpopulations in the cerebrospinal fluid (CSF). We investigated the frequency of cells positive for the surface markers CD4, CD8, CD25, CD45, CD69, and CD127 in 45 paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples by multiparameter flow cytometry from patients with MPD of the schizophrenic and affective spectrum with normal CSF cell counts and compared them with those from patients with non-inflammatory (NIND), chronic inflammatory (CIND) neurological disorders, and meningitis (MEN). In MEN patients, CD4+ cell frequency in PB, but not in CSF, was significantly increased as compared to CIND and NIND. No difference between patient groups was observed for CD8+. CD4+CD45RO+ double positive cells in PB were significantly lower in CIND than in MEN or NIND. The frequency of CD4+CD25+ cells in PB was significantly higher in MEN than in MPD or CIND. For CSF, the percentage of CD4+CD127(dim) cells was significantly lower in MEN than in MPD. CD4+CD127(dim) in PB and CSF showed overlapping characteristic clusters between MPD and CIND and MEN patients. Overall, the hypothesis of low degree inflammation in a subgroup of MPD is supported. The analysis of lymphocyte subsets in PB and CSF constitutes a novel promising tool to understand underlying pathomechanisms in psychiatric and neurological disorders on an individual case level.

Neocortical gray matter volume in first-episode schizophrenia and first-episode affective psychosis: a cross-sectional and longitudinal MRI study.

BACKGROUND: Overall neocortical gray matter (NCGM) volume has not been studied in first-episode schizophrenia (FESZ) at first hospitalization or longitudinally to evaluate progression, nor has it been compared with first-episode affective psychosis (FEAFF). METHODS: Expectation-maximization/atlas-based magnetic resonance imaging (MRI) tissue segmentation into gray matter, white matter (WM), or cerebrospinal fluid (CSF) at first hospitalization of 29 FESZ and 34 FEAFF, plus 36 matched healthy control subjects (HC), and, longitudinally approximately 1.5 years later, of 17 FESZ, 21 FEAFF, and 26 HC was done. Manual editing separated NCGM and its lobar parcellation, cerebral WM (CWM), lateral ventricles (LV), and sulcal CSF (SCSF). RESULTS: At first hospitalization, FESZ and FEAFF showed smaller NCGM volumes and larger SCSF and LV than HC. Longitudinally, FESZ showed NCGM volume reduction (-1.7%), localized to frontal (-2.4%) and temporal (-2.6%) regions, and enlargement of SCSF (7.2%) and LV (10.4%). Poorer outcome was associated with these LV and NCGM changes. FEAFF showed longitudinal NCGM volume increases (3.6%) associated with lithium or valproate administration but without clinical correlations and regional localization. CONCLUSIONS: Longitudinal NCGM volume reduction and CSF component enlargement in FESZ are compatible with post-onset progression. Longitudinal NCGM volume increase in FEAFF may reflect neurotrophic effects of mood stabilizers.

CSF somatostatin in affective illness.

Somatostatin is a hypothalamic tetradecapeptide with many actions. We investigated a potential role for somatostatinergic neuron dysfunction in affective disorder by measuring somatostatin in the CSF of 47 patients with affective illness and of 39 normal volunteers. Medication-free depressed patients showed significantly lower levels of CSF somatostatin than normal volunteers (P less than .001) or patients during the improved state (P less than .01). A significant inverse correlation was observed between somatostatin and the duration of sleep on the night of the lumbar puncture. We also observed significant correlations between somatostatin and 5-hydroxyindoleacetic acid and norepinephrine in the CSF. Also noted were the significance of depression-related decreases in CSF somatostatin in relation to information about central somatostatin secretion, reported abnormalities of somatostatin activity, and potential interactions between alterations in somatostatin activity and the pathophysiology of depression.

Cerebrospinal fluid somatostatin and psychiatric illness.

Somatostatin is a tetradecapeptide that is assuming increasing importance as a regulator of central nervous system activity. Originally identified as the hypothalamic growth hormone release-inhibiting factor, somatostatin has subsequently been shown to be extensively and selectively distributed throughout the central nervous system, to alter neuron excitability, to regulate and be regulated by the activity of classical neurotransmitters and neuropeptides, to exert a number of direct behavioral actions, and to display neuropsychiatric disorder-related alterations. In this article, a three-part study of cerebral spinal fluid (CSF) somatostatin in affective illness and schizophrenia is presented. In part 1, significant reductions in CSF somatostatin were observed in 49 bipolar and unipolar depressed patients relative to 47 controls. Values during depression were also significantly lower than those observed in affective disorder during the improved state or in schizophrenia. Diurnal studies involving paired AM and PM lumbar punctures revealed that depressed patients and normal volunteers had similar somatostatin values in the evening, despite having significantly different values in the morning. In part 2, the effects of several psychopharmacological agents on CSF somatostatin were examined, particularly the tricyclic anticonvulsant carbamazepine. A significant reduction of CSF somatostatin during treatment with carbamazepine was observed. The effect of carbamazepine on somatostatin could be related to its anticonvulsant, analgesic, or psychotropic effects. Part 3 deals with somatostatin as a major regulator of hypothalamic-pituitary-adrenal (HPA) axis activity. Somatostatin affects HPA activity by inhibiting, at a number of cellular levels, the stimulated release of adrenocorticotrophic hormone (ACTH) from the pituitary. A significant negative relationship between CSF somatostatin and the postdexamethasone plasma cortisol level in 22 depressed and 16 schizophrenic patients was observed. This relationship between low CSF somatostatin and escape from dexamethasone suppression was observed irrespective of diagnosis (i.e., depression or schizophrenia). Thus, there is indirect supporting evidence for a role for somatostatin dysregulation in the most consistently observed biological abnormality in depression, escape from dexamethasone suppression. Further study of somatostatin in neuropsychiatric disorders, and particularly depressive illness, offers great promise for better understanding their underlying affective, vegetative, cognitive, and physiological dysregulations.

Relationship between estimated premorbid adjustment and CSF homovanillic acid and 5-hydroxyindoleacetic acid levels.

The authors completed ratings of premorbid sexual and social adjustment and assays of the CSF homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and probenecid concentrations in 108 psychiatric patients. Among the 30 patients diagnosed as schizophrenic, poor premorbid sexual adjustment was associated with higher accumulations of HVA in the CSF. No relationship between the estimated premorbid social adjustment and CSF HVA levels was observed. These findings suggest that 1) sexual and social premorbid adjustment are partially independent variables, and 2) one of the biological correlates of sexual adjustment in schizophrenic patients may be the functional maturity of central dopamine systems.

CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa.

The authors examined the CSF GABA of 87 subjects: 29 normal control subjects, 11 patients with schizophrenia, 26 with depression, 6 with mania, and 15 with anorexia nervosa. Depressed patients had significantly lower CSF GABA levels than did normal subjects. This finding suggests that GABA may have a direct or indirect association with depressive affective disorders.

CSF monoamine metabolites in mania.

As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function.

CSF cortisol in patients with depression, mania, or anorexia nervosa and in normal subjects.

The authors studied CSF cortisol in 30 depressed patients, 10 manic patients, 21 women with anorexia nervosa, and 22 normal control subjects. All patients were also rated on a global severity scale for mania or depression. Results indicated higher CSF cortisol levels in all three patient groups than in the control group. Only the depressed group had a significant positive correlation between CSF cortisol and severity ratings. The authors recommend further research into the hypothalamic mechanisms associated with cortisol secretion and regulation.

CSF beta-endorphin-immunoreactivity in normal, schizophrenic, depressed, manic and anorexic subjects.

beta-Endorphin immunoreactivity was measured in cerebrospinal fluid of 75 medication-free subjects: normal, depressed, schizophrenic, and anorexic. No significant differences in beta-endorphin immunoreactivity were found. Affinity extraction chromatography revealed beta-lipotropin and beta-endorphin, but no apparent precursors.

Brain purinergic activity linked with depressive symptomatology: hypoxanthine and xanthine in CSF of patients with major depressive disorders.

The purine metabolites hypoxanthine and xanthine were analyzed in cerebrospinal fluid (CSF) of 70 patients with major depressive disorders (diagnosed according to Research Diagnostic Criteria) and, for reference, in 26 nonpsychiatric individuals. In the patient group, levels adjusted by analysis of covariance to same sex, age, height, and weight were univariately and multivariately correlated with both depressive subdiagnoses and individual depressive symptoms. Results indicate that raw CSF levels in depressed patients are significantly correlated with the four variables used in adjustment (for hypoxanthine mainly negatively with height; for xanthine mainly positively with age). Hypoxanthine and xanthine both appear to be linked with the expression of depressive symptomatology: lower levels of hypoxanthine are associated with anger and suicidal tendencies, and higher levels are related to memory disturbance; lower xanthine levels characterize patients with subjective feelings of depression, and in patients with higher levels appetite is poor.

Cerebrospinal fluid and plasma free cortisol concentrations in depression.

Cerebrospinal fluid (CSF) cortisol levels were examined in a total group of 65 patients. Those who were not depressed (ND), and those suffering from depressive neuroses (DN) had marginally elevated values. Patients with unipolar depression (UD) and bipolar depression (BD) had levels twice as high as the ND and DN patients. Psychotic UD and BD patients had the highest values, three to four times as high as the ND and DN subjects. A significant reduction of CSF cortisol levels was observed following treatment and recovery. Manic patients had moderately elevated CSF cortisol values. The CSF results were in good agreement with plasma total cortisol levels and with urinary free cortisol excretion. Age and sex effects were not responsible for the observed differences; similar results were found in patient subgroups studied in Australia and in the United States. Preliminary equilibrium dialysis data are presented for plasma and CSF cortisol binding. CSF cortisol was 20% bound and 80% free. Plasma free cortisol levels were in good agreement with CSF free cortisol values. Depressed patients have increased tissue and central nervous system (CNS) exposure to free, physiologically active glucocorticoids. The appearance of severe depressive symptoms which manifest a diurnal rhythm may be determined in part by excesssve CNS exposure to glucocorticoids.

Characteristics of patients with schizophrenia or neurological disorder and virus-like agent in cerebrospinal fluid.

A virus-like agent (V.L.A.) with a cytopathic effect on cultured cells was found in the cerebrospinal fluid of 18 of 47 patients with schizophrenia, of whom 10 had nuclear schizophrenic symptoms. In most patients with V.L.A., blood and C.S.F. protein concentrations were normal. Patients with and without V.L.A. had similar clinical characteristics but serum IgA levels were higher in those with V.L.A. V.L.A. was also detected in the C.S.F. of 8 of 11 patients with serious or chronic neurological disease (Huntington's chorea, multiple sclerosis, and unexplained alterations of consciousness).