Platelet serotonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women

Serotonin (5-hydroxytryptamine, 5-HT) is involved in the regulation of hypothalamic-pituitary-adrenal axis (HPA) activity and prolactin (PRL) secretion. The present study examined the relationship between platelet 5-HT and plasma cortisol and PRL concentrations in 20 schizophrenic, 25 depressed, and 25 healthy women. At the time of blood sampling, the schizophrenic and depressed patients had been drug-free for at least 7 days. Platelet 5-HT, plasma cortisol and PRL concentrations were determined by spectrofluorimetric, radioimmunoassay and immunoradiometric methods, respectively. Platelet 5-HT concentration was significantly higher in schizophrenic patients than in depressed patients or in healthy controls, while it was significantly lower in depressed patients than in healthy controls or in schizophrenic patients. Plasma cortisol levels were significantly increased both in schizophrenic and in depressed patients compared with values in healthy controls. Values of plasma PRL were similar across groups. A significant correlation was found between platelet 5-HT and plasma cortisol, and platelet 5-HT and plasma PRL concentrations in healthy controls, but not in schizophrenic or depressed patients. There was no significant relationship between plasma PRL and cortisol levels in any of the groups. Our data, although obtained on peripheral biochemical markers, indicate that depression and schizophrenia are characterized by disturbed 5-HT transmission and dysregulated HPA axis activity.     

Cardiac autonomic tone,plasma BDNF levels and paroxetine response in newly diagnosed patients of generalised anxiety disorder

Abstract

Objective: The study examined the effect on cardiac autonomic tone via heart rate variability (HRV), brain derived neurotrophic factor (BDNF) in newly diagnosed generalised anxiety disorder (GAD) cases with paroxetine-controlled release (PX) CR intervention.

Methods: Fifty GAD cases using DSM-5 criteria, matched with healthy controls (HC) were assessed with clinical measures (Hamilton Anxiety Scale (HAM-A), Clinical Global Impression- Severity Scale (CGI-Severity), General Health Questionnaire -12 (GHQ-12), HRV, plasma BDNF levels initially and 6?weeks postintervention with paroxetine CR.

Results: HRV parameters were significantly lower in GAD vs HC at baseline for standard deviation of normal to normal intervals (SDNN) and proportion of differences in consecutive NN intervals that are longer than 50?ms (pNN50). Significantly higher plasma BDNF levels were noted between HC versus GAD at baseline. Postintervention HAM-A, CGI scores, GHQ-12 item scores showed significant reduction. Significant differences also noted in square root of mean squared difference of successive NN intervals (RMSSD), (SDNN), pNN50 and in plasma BDNF levels after intervention within GAD group. Significant negative correlation observed between HAM-A scores and SDNN parameter after taking PX CR in GAD.

Conclusion: GAD showed cardiac autonomic dysfunction, lowered plasma BDNF levels and their improvement with paroxetine CR.

• Key message

• GAD is associated with significantly lower HRV, suggestive of cardiac autonomic dysfunction and lowered plasma BDNF levels, an indicator of stress.

• Therapeutic intervention with Paroxetine in GAD patients showed clinically significant improvement reflecting restoration of the cardiac autonomic tone and BDNF levels, thus implying their role as potential biomarkers.

     

Measurement of plasma homovanillic acid concentrations in schizophrenic patients

1. Several lines of evidence suggest that abnormalities of central dopaminergic transmission may be involved in the expression of some schizophrenic symptoms. However, elucidation of the role of dopamine (DA) in schizophrenia has eluded investigative efforts partially because no accurate and easily repeatable measure of brain DA activity exists. 2. The development of a technique to measure homovanillic acid in plasma has offered the possibility of performing serial measurements of this major DA metabolite. 3. Assuming that plasma homovanillic acid (PHVA) concentrations is an index of brain DA activity, measurement of PHVA can play a role in elucidating the DA abnormality in schizophrenia. 4. Results to date suggest that plasma homovanillic acid concentrations are lower in chronic schizophrenic patients compared to normal controls, and that PHVA values correlate with schizophrenic symptom severity. 5. In addition, PHVA levels were shown to initially rise and subsequently decline during chronic neuroleptic administration in treatment responsive but not in treatment refractory schizophrenic patients.     

Effect of apomorphine on growth hormone and prolactin secretion in schizophrenic patients, with or without oral dyskinesia, withdrawn from chronic neuroleptic therapy.

Serum growth hormone (GH) and prolactin (PRL) concentrations were measured after administration of the dopamine receptor agonist, apomorphine HC1 (0.75 mg subcutaneously), to 17 chronic schizophrenic patients, four of whom had an oral dyskinesia, who were withdrawn from chronic neuroleptic therapy for periods of two to 15 weeks, and in 21 control subjects (normal volunteers or physically healthy alcoholics not exposed to neuroleptics). Six of the schizophrenic patients, but none of the controls, had raised baseline levels of GH (greater than 6 ng/ml). After apomorphine all controls showed an increase in serum GH with a peak concentration of 9 ng/ml or more, whereas eight subjects withdrawn from neuroleptics showed an inadequate response (peak less than 6 ng/ml) and in two others an inadequate response was obtained on one of two trials. The peak GH concentration was significantly less after apomorphine in patients withdrawn from neuroleptics (11.90 +/- 3.19 ng/ml) compared with controls (20.80 +/- 2.11 ng/ml) (P less than 0.05). Among patients withdrawn from neuroleptics, those with an oral dyskinesia had significantly lower peak GH concentration 2.46 +/- 0.93 ng/ml) after apomorphine compared with those without (14.85 +/- 3.83 ng/ml) (P less than 0.05). There were no differences in serum PRL concentrations, before or after apomorphine administration, between patients withdrawn from neuroleptics and controls. In uncontrolled observations none of the four patients with an oral dyskinesia showed any worsening of the movement disorder after apomorphine. These data provide no evidence for supersensitivity of dopamine receptors in chronic schizophrenic patients withdrawn from chronic neuroleptic therapy.     

Interleukin-6-(IL-6) plasma levels in depression and schizophrenia: comparison between the acute state and after remission

The concentration of cytokines such as Interleukin-6 (IL-6) has been reported to be elevated in depressed and schizophrenic patients and, in healthy persons, upon stress. Interleukin-6 plasma levels were determined in depressed (n = 12) and schizophrenic (n = 32) patients during the acute state of illness and after remission at approximately 8 weeks after admission and were compared with healthy controls (n = 12). Patients were diagnosed according to DSM-III-R by the Structured Clinical Interview (SLID). Severity of illness was assessed for depression by the Montgomery Asberg Depression Rating Scale (MADRS) and for schizophrenia by the Brief Psychiatric Rating Scale (BPRS). Interleukin-6 plasma concentrations were elevated during the acute state either of depression or of schizophrenia if compared to controls. After remission, IL-6 concentrations in depressed and in schizophrenic patients had decreased and did not differ significantly from controls. We hypothesize that the elevated IL-6 levels during the acute state of depression or schizophrenia may reflect an unspecific stress response.     

Plasma 3-methoxy-4-hydroxyphenylglycol changes associated with clinical state and schizophrenic subtype

In a study of 14 drug-free schizophrenic patients and 22 healthy control subjects, the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) level appeared to be altered by changes in clinical state. Repeated sampling in schizophrenic patients showed that plasma MHPG values were elevated in high-psychosis phases in comparison with metabolite levels at times of lower psychosis. There was a nonsignificant trend toward higher MHPG levels in paranoid schizophrenic patients in comparison with patients who had undifferentiated schizophrenia. Paranoid schizophrenic patients had significantly elevated plasma MHPG levels in comparison with previously studied healthy controls. These findings suggested that alterations in the plasma MHPG level may reflect psychosis-related changes in norepinephrine function in schizophrenia.     

Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements

Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD). Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) plays a critical role in the maintenance of functional neurons. The present study was to examine plasma BDNF levels and the relationship among BDNF level, psychopathological and tardive dyskinesia symptoms in schizophrenic patients with TD. Eighty schizophrenic patients with TD were compared with 45 schizophrenic patients without TD, as well as with 45 age-, sex-matched normal controls. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). The psychopathology of patients was assessed by the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the patients with TD had lower plasma BDNF levels than those without TD, and than that of normal controls. In the patients with TD, plasma BDNF levels was inversely correlated with AIMS total score, and with PANSS negative subscore. Female patients had significantly lower plasma BDNF levels than male TD patients. Our results suggest that decreased BDNF may play an important role in the pathophysiology of TD. There may be a relationship between decreased BDNF levels and dyskinetic movements associated with TD.     

Blood protein fraction comparisons of normal and schizophrenic patients.

Whole blood, plasma, or serum levels of various components were measured in fasting, drug-free control subjects and drug-free schizophrenic patients. Compared to normal controls, chronic schizophrenic patients showed increased alpha2-globulins and decreased plasma cholinesterase activity and ceruloplasmin activity, and acute schizophrenic patients showed decreased alpha2-globulins. Compared to chronic patients, acute schizophrenics showed decreased alpha2-globulins and IgA. Compared to normal controls of similar age, chronic schizophrenic patients weighed less, were shorter, and had smaller body surface area. The acute schizophrenic patients were significantly younger than the normal subjects or chronic schizophrenics but there was no difference in the other physical measurements. The present study indicates no gross disturbances in the blood variables studied. That some differences are statistically significant from controls is of scientific interest, but of no clinical value in the diagnosis of schizophrenia.     

Lymphocyte monoamine oxidase and plasma prolactin and growth hormone in tardive dyskinesia

Twelve elderly women with tardive dyskinesia were matched with 12 patients without dyskinesia. Lymphocyte monoamine oxidase (MAO) activity and plasma prolactin and growth hormone concentrations were determined "blind" in these 12 pairs of patients. Chronic schizophrenic patients with tardive dyskinesia had significantly lower lymphocyte MAO activity as compared to controls. Organic brain syndrome patients with dyskinesia did not differ from controls in the lymphocyte MAO activity. These results with lymphocyte MAO parallel our earlier findings on platelet MAO. No significant differences were found between dyskinesia group and controls in the plasma prolactin and growth hormone concentrations. Possible implications of our findings are discussed.     

Tissue culture evidence for a circulating neurotoxin in Huntington's chorea

We explored with tissue culture techniques the possibility that a circulating neurotoxin might cause the premature loss of certain populations of neurons that characterizes Huntington's chorea (HC). Explants of striatum from newborn rats were grown in culture media containing 30% by volume of serum from drug-free HC patients or from healthy control subjects. Glutamic acid decarboxylase (GAD), the enzyme which synthesizes gamma-aminobutyric acid (GABA), was later assayed in these explants as an indicator of the health of GABAergic striatal neurons. The sera of 7 of 8 HC patients decreased GAD activity markedly when present as 30% of the tissue culture medium. When present in lower concentration (15%), HC sera either decreased or increased GAD activity in explants. Deproteinization of sera with perchloric acid did not abolish these effects on GAD activity. A depressant effect on GAD activity was detected in the cerebrospinal fluid of 1 of 4 HC patients tested. These experiments suggest the presence of a circulating neurotoxin, possibly excitotoxic to GABAergic striatal interneurons, and probably a small molecule. Identification of this substance could lead to an effective preventive treatment for persons genetically at risk for HC.     

Altered antioxidant defense system in clinically stable patients with schizophrenia and their unaffected siblings

Objective

To determine Red Blood Cell (RBC) antioxidant enzyme activities and plasma Thiobarbituric Acid Reactive Substances (TBARS) in clinically stable patients with schizophrenia and their unaffected siblings.

Methods

A case-control study carried out on three groups: 60 schizophrenic patients treated with neuroleptics, 33 of their unaffected siblings and 30 healthy controls with no family psychiatric history. Biological markers were measured on fasting patients after a period of tobacco abstinence: RBC antioxidant enzyme activities – superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) – by spectrophotometry and plasma levels of TBARS by spectrofluorimetry.

Results

RBC SOD and CAT activities were significantly lower in schizophrenic patients and their unaffected siblings compared to the control group (P < 0.001). Schizophrenic patients also had significantly lower RBC GSH-Px activity than controls (P = 0.03), whereas their unaffected siblings had significantly higher RBC GSH-Px activity than controls (P = 0.04). Plasma TBARS were higher in schizophrenic patients than their unaffected siblings: 2.1 ± 0.8 μmol/l vs. 1.7 ± 0.6 μmol/l (P = 0.06).

Conclusions

Our results showed a decrease in antioxidant enzyme activities and an increase in lipid peroxidation confirming the existence of oxidative stress in schizophrenic patients treated with neuroleptics. Additionally, this suggests that the increase in GSH-Px activity in unaffected siblings would be a protective mechanism against oxidative stress and damage. Other studies are necessary to confirm these findings.     

Plasma serine in schizophrenics and controls measured by gas chromatography-mass spectrometry.

In several previous studies, we reported significantly higher plasma serine concentrations in psychotic (and schizophrenic) subjects compared with nonpsychotic and control subjects. In those studies, we used a gas chromatography technique to assay the amino acids. Perry and Hanson (1985), using cation-exchange chromatography to assay plasma amino acids, found no differences in the plasma serine concentrations of controls compared with schizophrenic patients. They criticized our work on technical grounds and suggested that some other substance was co-eluting with the gas chromatographic serine peaks in our assays. We have now examined the plasma of schizophrenic and control subjects with gas chromatography-mass spectrometry (GC-MS), where accurate amino acid quantitation relative to a known internal standard can be achieved. The results show that the plasma serine concentrations of schizophrenic patients are significantly higher than those of controls. Also, plasma glycine concentrations are significantly higher in schizophrenic patients compared with controls.     

RBC and plasma choline in neuroleptic-treated schizophrenic patients

We measured red blood cell (RBC) choline and plasma choline concentrations in 27 chronic schizophrenic inpatients and 23 normal controls. Both blood choline measures had a significant test-retest reliability in patients whose neuroleptic status remained unchanged over 1 month. RBC choline concentration was significantly lower in patients medicated with neuroleptics and cogentin. Patients with a low RBC choline and a low RBC/plasma choline ratio were on significantly higher doses of medication and had higher scores on the hostility/suspiciousness subscale of the Brief Psychiatric Rating Scale. RBC choline increased when neuroleptics were discontinued. Blood choline measures were also compared among medication-free schizophrenic patients, inpatients with other diagnoses, and normal controls. No significant differences were seen among these groups for any choline measure, although the schizophrenic patients showed greater variability. Medication-free schizophrenic patients with such clinical factors as tardive dyskinesia and abnormalities on computed tomography contributed to this variability. Age was positively correlated with plasma choline.     

焦虑症的生化病理机制探讨

目的：从神经递质与神经内分泌角度探讨焦虑症的生化病理机制。方法：采用高效液相色谱法及放射免疫测定法，分别测定25例焦虑症患者和28例正常对照者血小板5—羟色胺(5—HT)含量及血浆催乳素(PRL)含量、地塞米松抑制实验(DST)皮质醇含量。结果：广泛性焦虑(GAD)组血小板5—HT水平高于正常对照组，惊恐障碍(PD)组与正常对照组无显著差异；GAD组与对照组血浆PRL均极显著低于PD组；GAD组与PD组血浆基础皮质醇含量均显著高于正常对照组，两组DST阳性率均为20％，正常对照组为14．3％，3组阳性率无显著性差异；汉密尔顿焦虑量表(HAMA)评分与血浆皮质醇浓度呈显著正相关。结论：焦虑症患者存在神经递质和神经内分泌功能的紊乱，但不同亚型间可能存在不同的病理机制，皮质醇浓度可能是焦虑水平的标志因子。     

Th1, Th2 and Th3 cytokine alteration in schizophrenia

BACKGROUND: Several studies have shown that there is an imbalance between T helper 1 (Th1) cytokines and T helper 2 (Th2) cytokines in patients with schizophrenia. The T helper 3 (Th3) cytokine, transforming growth factor beta-1 (TGF-beta1), has been shown to suppress the production of Th1 cytokines. Therefore it is hypothesized that it may play a role in schizophrenia by suppressing overactive Th1 system. METHODS: We recruited 88 schizophrenic patients and 88 matched controls. The basal plasma concentrations of IFN-gamma (Th1), IL-4 (Th2) and TGF-beta1 (Th3) were studied at the time the patients were admitted to the hospital and following 8 weeks of treatment with antipsychotics. RESULTS: The detection rate of plasma IFN-gamma and basal plasma TGF-beta1 level were significantly higher in schizophrenic patients than in controls whereas detection rate of plasma IL-4 was lower in patients. The ratio of Th1/Th2 cytokines (IFN-gamma/IL-4) was higher in schizophrenic patients. Following the neuroleptic treatment, the IFNgamma and TGF-beta1 levels returned to control values, and IL-4 concentration rose above the control value. CONCLUSION: Schizophrenic patients showed higher Th1/Th2 ratio which is attenuated by effective neuroleptic treatment. It is possible that TGF-beta1 plays a role in reducing the activity of Th1 cytokine.     

Free and conjugated plasma homovanillic acid in schizophrenic patients

It has recently been suggested that the plasma level of homovanillic acid (HVA) may provide an index of central dopaminergic activity in humans. Clinical studies have shown that in schizophrenic patients, plasma HVA levels increase with the severity of psychopathology. However, these studies only considered the plasma free HVA fraction whereas investigations on conjugated HVA in humans are sparse and results remain controversial. The aim of this study was to measure both plasma free and conjugated HVA in healthy volunteers and drug-free schizophrenic patients. The mean values and the ranges of plasma free HVA in volunteers and patients were similar to those described in the literature. A substantial and significant increase in plasma free HVA was observed in schizophrenic patients compared with normal subjects. In contrast, plasma conjugated HVA was significatively decreased in schizophrenics. The plasma total HVA was nevertheless higher in schizophrenics compared with controls. No significant correlations were observed between plasma HVA levels and the clinical features of schizophrenic patients rated by various psychiatric scales. These findings suggest that there is an imbalance between plasma free and conjugated HVA in schizophrenic patients, who present an increase in total HVA when compared with controls. Paranoid schizophrenic patients, who present mainly positive symptoms, show the most marked plasma free/conjugated HVA imbalance.     

GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum

BACKGROUND: Glutamic acid decarboxylase (GAD) is the rate limiting enzyme responsible for conversion of glutamate to gamma-aminobutyric acid (GABA) regulating levels of glutamate and GABA in the mammalian brain. Reelin is an extracellular matrix protein that helps in normal lamination of the embryonic brain and subserves synaptic plasticity in adult brain. Both GAD and Reelin are colocalized to the same GABAergic interneurons in several brain sites. We hypothesized that levels of GAD and Reelin would be altered in cerebellum of subjects with schizophrenia and mood disorders differentially vs. controls. METHODS: We employed SDS-PAGE and Western blotting to measure levels of GAD isomers 65 and 67 kDa and Reelin isoforms 410-, 330- and 180-kDa proteins as well as beta-actin in cerebellum of subjects with schizophrenia, bipolar disorder and major depression vs. controls (N = 15 per group). RESULTS: GAD 65- and 67-kDa levels were decreased significantly in bipolar, depressed and schizophrenic subjects (p < 0.05) vs. controls. Reelin 410- and 180-kDa proteins decreased significantly (p < 0.05) in bipolar subjects vs. controls. Reelin 180 kDa was decreased significantly (p < 0.05) in schizophrenics vs. controls. beta-Actin levels did not vary significantly between groups. There were no significant effects of confounding variables on levels of various proteins. CONCLUSION: This study demonstrates for the first time significant deficits in GABAergic markers Reelin and GAD 65 and 67 proteins in bipolar subjects and global deficits in the latter proteins in schizophrenia and mood disorders, accounting for the reported alterations in CSF/plasma levels of glutamate and GABA in these disorders.     

Impaired presynaptic regulation of norepinephrine in schizophrenia. Effects of clonidine in schizophrenic patients and normal controls

Recent studies have found elevated levels of norepinephrine (NE) in CSF and brain specimens from schizophrenic patients. Presynaptic inhibitory alpha 2-adrenergic receptors regulate NE release in the brain. The hypothesis that the functional sensitivity of this presynaptic regulation of NE is impaired in schizophrenia was tested by evaluating, in schizophrenic patients and age-matched normal controls, the ability of clonidine, an alpha 2 agonist, to lower plasma levels of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and to lower blood pressure (BP). Clonidine produced a significant decrease in plasma MHPG levels in the normal control group, but did not lower plasma MHPG levels in the schizophrenic patients. Clonidine decreased BP equally in both groups. These results suggest that there is a functional subsensitivity of the inhibitory presynaptic alpha 2-adrenergic receptor in schizophrenia, which may relate to an impaired regulation of NE turnover.     

Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia

Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia.