Systemic concentration of apelin, but not resistin or chemerin, is altered in patients with schizophrenia.

It has been suggested that immune-inflammatory processes might be involved in the etiopathogenesis of schizophrenia. Since growing evidence indicates that adipokines strongly modulate the course of immune response and inflammatory processes, it is currently suggested the contribution of those factors in the etiology of schizophrenia as well. The aim of this study was to determine the serum levels of 4 adipokines-apelin, resistin, chemerin, and omentin-in patients with schizophrenia as compared with healthy subjects. Fifty-seven adult patients with schizophrenia and 31 healthy volunteers were included in this prospective study. ELISA was used to measure the serum concentration of resistin, apelin, omentin-1, and chemerin. No difference in the mean concentration of resistin (p=0.20) and chemerin (p=0.30) between patients with schizophrenia and the healthy group was observed. Apelin concentration was significantly (p=0.004) lower in patients with schizophrenia as compared with controls. A significant difference in apelin level between men with schizophrenia and control group (p=0.04) was reported. Apelin concentration was significantly correlated with waist-to-hip ratio, whereas chemerin concentration was significantly correlated with the Positive and Negative Syndrome Scale G score. There exists evidence that apelin might be involved in the pathogenesis of schizophrenia.

Cognitive deficit in patients with paranoid schizophrenia: Its clinical and laboratory correlates.

The aim of this study was to search for correlates of cognitive impairment in patients with paranoid schizophrenia among clinical, demographic, anamnestic and biochemical markers (NSE, S100B protein, BDNF, hs-CRP). Patients with paranoid schizophrenia (n=125) were examined using the Brief Assessment of Cognitive Function in Schizophrenia, the Rey-Osterrieth Complex Figure task, and a number of clinical scales including the Positive and Negative Syndrome Scale. The majority of patients demonstrated cognitive impairment. The type of impairment was highly heterogeneous and individual. Relationships were found between the degree of executive functioning and family history of mental illness; working memory and age of onset of schizophrenia; and visual memory and psychopathological symptomatology. Negative and affective symptoms were not significantly associated with cognitive functioning. Treatment with first generation antipsychotics was associated with a more frequent impairment of motor skills, and concomitant anticholinergic drugs, with reduced accuracy. Use of second-generation antipsychotics only was associated with better accuracy, working memory and speech fluency. Among the patients, 21.4% had signs of a systemic inflammatory response, indicating a possible role of inflammatory response in the development of schizophrenia. CRP, S100B and NSE levels reflected features of the course of illness and therapeutic response. Patients with lower concentrations of BDNF were characterized by lower processing speeds.

A defect in the antioxidant defense system in schizophrenia.

OBJECTIVES: Several oxidants and antioxidants have been evaluated in schizophrenia. However, previous studies frequently focused on individual parameters. Determination of the total oxidant and antioxidant status may be more useful. Therefore, we aimed to evaluate both plasma total oxidant status (TOS) and total antioxidant status (TAS) together with the oxidative stress index (OSI) in schizophrenia patients for the first time in the literature. METHODS: A total of 60 schizophrenia patients and 40 healthy volunteers were included in the study. The Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-severity scale (CGI-S) were used to evaluate the severity of schizophrenia in the patients. TOS and TAS were measured in plasma and the OSI was calculated for patients and controls. RESULTS: There was no difference between patients and controls with regard to TOS, but the patients' TAS and OSI were significantly lower and higher, respectively, than those of the controls. No difference was detected between the schizophrenia subtypes or between the patients on typical or atypical antipsychotic medications or a combination of the two with regard to oxidative parameters. There was a weak to moderately significant negative correlation between TAS and total, positive and general psychopathology PANSS scores. Finally, we found a weak to moderately significant negative correlation between the CGI-S score and TOS and between the CGI-S score and TAS. CONCLUSIONS: There is a defect in the antioxidant defense system in schizophrenia. Known oxidative stress that causes oxidative cell damage and thus contributes to the pathophysiology of schizophrenia may be mainly related to this defensive defect.

Decreased serum levels of interleukin-2 and interleukin-6 in Indian Bengalee schizophrenic patients.

BACKGROUND AND PURPOSE: Autoimmune process is thought to be involved in the pathophysiology in some cases of schizophrenia. Alteration in interleukin (IL) regulation is regarded as additional proof of autoimmunological background in schizophrenia. Most of the research in interleukin activity in schizophrenia has been in Caucasian and some Mongoloid patients. We have studied the serum IL-2 and IL-6 level in psychotropic medication free and antipsychotic medicating schizophrenic patients who are Indian Bengalee by ethnicity. METHOD: Twenty psychotropic medication free and 30 antipsychotic medicating schizophrenic patients who fulfilled DSM-IV-TR criteria and 30 of the same age and sex matched controls were recruited. Serum level of IL-2 and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). RESULT: There was a significant decrease of IL-2 and IL-6 in both antipsychotic medicating and psychotropic medication free patients. Further the medicating patients showed lower level of IL-2 and IL-6 than the psychotropic medication free patients. CONCLUSION: This is the first study to describe a decrease serum level of IL-6 in schizophrenic patients. The study provides the evidence that some kind of immune dysregulation is involved in pathophysiology of schizophrenia. The study also provides the evidence for the immunosuppressive effect of antipsychotic drugs.

[The mRNA expression levels of IL-1beta, TNF-alpha and tyrosine hydroxylase in peripheral blood of paranoid schizophrenic patients].

AIM: To investigate the gene expression levels of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and tyrosine hydroxylase (TH) in peripheral blood of paranoid schizophrenic patients, and explore the neuroimmunological mechanism of paranoid schizophrenia. METHODS: The mRNA expression levels of IL-1beta, TNF-alpha and TH in the peripheral blood of 39 paranoid schizophrenic patients and 30 normal controls were measured with RT-PCR and semi-quantitative technique. RESULTS: The mRNA expression levels of IL-1beta, TNF-alpha and TH was higher in paranoid schizophrenic patients than those in normal controls (P<0.01). The correlation between the gene expression levels of IL-1beta and TH was found in normal controls (r=0.666, P<0.01), not in paranoid schizophrenic patients (P>0.05); and the correlation between the gene expression levels of IL-1beta and TNF-alpha was significant in all groups (r=0.847 for normal controls and 0.942 for patients, P<0.01, respectively). CONCLUSION: Pro-inflammation cytokines and catecholamines have been demonstrated to be overexpressed in the peripheral blood of paranoid schizophrenic patients. And the correlation between catecholamines and pro-inflammation cytokines, which exists in the controls, is broken in paranoid schizophrenic patients.

Prolactin and estradiol serum levels in unmedicated male paranoid schizophrenia patients.

There is evidence for the involvement of the endocrine system in schizophrenia. This involment was widely investigated in female patients. In the current study, we examined prolactin and estradiol serum levels in hospitalized unmedicated men with first-episode and recurrent schizophrenia and then tested possible correlation with various subtypes of the disease. In addition, the estradiol and prolactin levels were compared with a healthy control group. The serum samples were assessed the morning following admission in fifty-seven schizophrenia male patients. There was a significant difference in prolactin serum levels between the paranoid and "nonparanoid" schizophrenia subgroups. However, no significant differences were found in estradiol serum levels between schizophrenia subtypes or between the patients and their healthy counterparts. Finally, a significant and positive correlation was found between the prolactin and estradiol levels in the paranoid subgroup alone. Thus, it appears that low estradiol levels are associated with low prolactin levels, alleged hyperdopaminergic tone and psychotic breakdown in paranoid schizophrenia. The results of the present study further support our previous report of the association between prolactin serum levels and the schizophrenia cluster subtypes, indicating a different dopaminergic activity for the various forms of the disease.

Influence of clozapine on platelet serotonin, monoamine oxidase and plasma serotonin levels.

The purpose of this study was to investigate the influence of clozapine on plasma serotonin, platelet serotonin and monoamine oxidase (MAO) levels in schizophrenic patients and to compare their results with those of unmedicated healthy controls. Groups of 20 outpatients with schizophrenia and 20 healthy controls matched for age, sex and smoking status were recruited for the study. Psychopathology, neurocognitive functioning, plasma serotonin, platelet serotonin and MAO levels were assessed after 1-week drug free interval, and 8 weeks after initiation of clozapine treatment in an open design. The mean clozapine dose at week 8 was 382.5+/-96.4 (range: 250-600) mg/day. In the patient group, at baseline, plasma serotonin and platelet MAO levels were significantly lower, and platelet serotonin levels were significantly higher than in controls. After 8 weeks of clozapine treatment, plasma serotonin and platelet MAO levels increased significantly, while a significant decrease in platelet serotonin levels was detected compared with baseline values. Baseline platelet MAO levels explained 22% of the variance in Clinical Global Impression - Improvement (CGI-I) and improvement in attention, while baseline platelet serotonin predicted 23% of the variance in the improvement in positive symptoms during clozapine treatment. Our data indicate that clozapine may be reversing or compensating for a pre-existing alteration in serotonergic neurotransmission in schizophrenic patients. The prediction of response to clozapine through peripheral biochemical markers may have important clinical implications if repeated in larger samples.

A prospective study of serum ghrelin levels in patients treated with clozapine.

We investigated serum ghrelin levels (SGL) in 12 patients with schizophrenia over a 10-week period after initiation of clozapine treatment. In contrast to increments of body mass indices (BMI, kg/m2) and serum leptin levels (SLL), no significant change in SGL was detected. Inverse correlations between delta SGL and delta SLL did not reach statistical significance. Linear mixed model analysis could not detect effects of age, sex, BMI, SLL and serum clozapine levels on SGL. Our results do not support a causal involvement of ghrelin in clozapine-related weight gain.

Male patients with paranoid schizophrenia have greater ACTH and cortisol secretion in response to metoclopramide-induced AVP release.

Dynamic testing of the hypothalamic-pituitary-adrenal axis in schizophrenia has yielded conflicting results, which may be related to patient selection and previous exposure to psychotropic medication. The objective of this study was to determine the pattern of corticotropin (ACTH) and cortisol release in response to metoclopramide (a dopamine antagonist), which appears to be unique in its ability to release vasopressin (AVP), in drug naive patients with schizophrenia experiencing their first episode of psychosis. In this study, we examined AVP, ACTH and cortisol release in response to metoclopramide in 10 drug-naive, first-episode male patients with a DSM IV diagnosis of paranoid schizophrenia and compared them to healthy control subjects matched for age, sex and smoking status. Patients, as compared to controls had higher levels of baseline plasma cortisol (375.5+/-47.4/l vs. 273.8+/-42.2 nmol/l, respectively; t=2.48, df=9, p< 0.02) and plasma ACTH (14.9+/-0.85 vs. 11.3+/-0.57 pg/ml, respectively; t=4.29, df=9, p<0.001). AVP levels were lower in patients though this did not reach statistical significance (0.89+/-0.09 vs. 1.3+/-0.08 pmol/l, respectively; t=1.97, df=9, p<0.07). A repeated measures 2-way ANOVA to compare responses to metoclopramide over time between the two groups yielded a significant group by time interaction for cortisol (F=11.3, df=6, 108, p<0.001) and ACTH (F=15.65, df=6, 108, p<0.002). Post hoc Tukey's test revealed significant differences between the two groups at +30, +45, +60, +90 and +120 min for cortisol (p<0.01) and at +30, +45, +60 and +90 min for ACTH (p<0.01). The group by time interactions continued to remain significant when cortisol (F=10.9, df=6, 107, p<0.001) and ACTH (F=13.04, df=6, 108, p<0.002) were entered as co-variates. There was a significant positive correlation between AVP and cortisol responses in patients (r=0.65, df=8, p<0.01). Male patients with paranoid schizophrenia release greater amounts of ACTH and cortisol in responses to metoclopramide-induced AVP secretion than control subjects.

[Effect of clozapine and risperidone on serum cytokine levels in patients with first-episode paranoid schizophrenia].

OBJECTIVE: To study the effects of clozapine and risperidone on serum cytokine levels in patients with first-episode paranoid schizophrenia, and explore the role of the cytokines in the psychopathological basis of the illness. METHOD: Fifty-eight patients with first-episode paranoid schizophrenia were treated with either clozapine or risperidone, and before and at the end of the 4th, 8th weeks and 6th months after the medication respectively, the serum levels of interleukin (IL)-6, 2, 18,and tumor necrosis factor (TNF)alpha were measured with enzyme-linked immunosorbent assay (ELISA). The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the psychotic symptoms. RESULT: In patients treated with risperidone, the levels of serum IL-6 and IL-2 after 4 weeks, TNFalpha after 8 weeks, and IL-18 after 6 months were all significantly lowered in comparison with the pretreatment levels (P<0.01 or 0.05). In clozapine group, the levels of IL-2 after 4 weeks and IL-6 and IL-18 after 6 months were lowered significantly (P<0.01 or 0.05). Before the medication, serum IL-6 level was positively correlated with Positive Syndrome scores (r=0.386, P<0.01), IL-2 with the total score and Positive Syndrome scores (r=0.338, 0.305; P<0.01, 0.05), and TNFalpha with the total score (r=0.283, P<0.05). The changes of IL-2 and IL-6 after 8 weeks was positively correlated with the change of Positive Syndrome scores (r=0.268, 0.375; P<0.05, 0.01). Six months after the medication, the change in IL-6 and TNFalpha levels was positively correlated with the change of total score (r=0.365, 0.362; P<0.05). Before treatment, IL-6 was positively correlated with IL-2 levels (r=0.356, P<0.01), and TNFalpha with IL-18 levels (r=0.291, P<0.05). TNFalpha was positively correlated with IL-6 levels (r=0.332, P<0.01) 8 weeks after the medication. The changes in IL-6 was positively correlated with the those in IL-2 levels 6 months after the medication (r=0.391, P< 0.05). CONCLUSION: Clozapine and risperidone have similar immunosuppression actions and may affect serum IL-6 levels in patients with paranoid schizophrenia, in the psychopathology of which the cytokines play their roles of various importance.

Elevated expression of integrin alpha(IIb) beta(IIIa) in drug-naïve, first-episode schizophrenic patients.

BACKGROUND: Patients with schizophrenia have an increased risk over the general public of developing cardiovascular illness. It is unknown if there are functional changes in platelet surface receptors in schizophrenia. We therefore analyzed the surface expression of glycoprotein (GP)Ib, the integrin receptor alpha(IIb)beta(IIIa), CD62 (P-selectin), and CD63, and investigated platelet function in schizophrenic patients compared with healthy volunteers. METHODS: Nineteen drug-naive, first-episode patients with a DSM IV diagnosis of paranoid schizophrenia were compared with matched healthy controls. Flow cytometry was used to assess platelet surface expression levels of GPIb, alpha(IIb)beta(IIIa), CD62, and CD63. Adenosine diphosphate-induced platelet aggregation was assayed. RESULTS: The schizophrenic patients had a significantly (p < .0001) increased number of 68,145 +/- 8,260.1 alpha(IIb)beta(IIIa) receptors, platelet compared with 56,235 +/- 8,079.4 receptors, platelet in healthy controls. CONCLUSIONS: Patients with schizophrenia have increased platelet expression of alpha(IIb)beta(IIIa), which may contribute to their increased risk of cardiovascular illness compared with the general population.

[Structural-metabolic characteristics of erythrocyte membrane in patients with paranoid schizophrenia undergoing psychopharmacotherapy]. / Strukturno-metabolisheskie osobennosti membrany éritrotsitov u bol'nykh paranoidnoi shizofreniei v usloviiakh psikhofarmakoterapii.

Structural features of the hydrophobic compartment and external parts of the erythrocyte membrane, Na+ and K+ ATPase activity, intensity of the free-radical oxidation of lipids, and the surface relief of erythrocytes were studied in paranoic schizophrenia patients before and after a course of pharmacotherapy. It was established that the administration of neuroleptics in therapeutic doses does not cause damage of the erythrocyte membrane.

Investigation of serum cytokine levels and cytokine production in whole blood cultures of paranoid schizophrenic patients.

There is some evidence that the pathophysiology of schizophrenia is related to changes in the innate and adaptive immune systems. In an attempt to define a potential immunological dysfunction in schizophrenia, we measured the serum levels of several cytokines in the sera of 24 patients with paranoid schizophrenia and investigated the cytokine production in whole blood assays after stimulation in vitro with virus (Newcastle disease), phytohemagglutinin (PHA) or bacterial lipopolysaccharide (LPS) and compared them with healthy, normal controls. A significant increase of interleukin 6 (IL-6), IL-8 and interferon gamma (IFN-gamma) levels, but a decreased L-10 level were observed in the sera of patients with schizophrenia. No significant changes in the serum levels of IL-2, IL-4, IFN-alpha and tumor necrosis factor alpha (TNF-alpha) were detected in these patients. When cytokine production in vitro was examined, a significant defect in PHA-induced IL-2, L-4 and IFN-gamma, and in virus-induced IFN-alpha production, but no significant alterations in LPS-induced IL-6, IL- 10 and TNF-alpha production were observed. In summary, increased serum levels of some cytokines such as IL-6, IL-8 and IFN-gamma indicate an activation of the inflammatory response in schizophrenia, while the in vitro assay indicates significant changes in the Th1 (decreased production of 1L-2 and IFN-gamma) and Th2 (decreased production of IL-4) cell system responses. The role of the defective EFN-alpha production in the regulation of the imbalance between Th1 and Th2 cell system responses is suggested.

Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients.

RATIONALE: Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established. OBJECTIVE: We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response. METHODS: Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design. RESULTS: Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations. CONCLUSIONS: These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.

Prolactogenic effects of risperidone in male patients--a preliminary study.

This preliminary study describes a case of a male patient who developed gynaecomastia and sexual difficulties whilst taking risperidone for chronic paranoid schizophrenia. Laboratory tests showed raised prolactin levels and depressed testosterone levels which were reversed on cessation of medication. A small study was subsequently conducted on male psychotic patients to compare the prolactogenic effects of risperidone (n=14) with traditional antipsychotic medication (n=15). The results showed a greater but non-significant prolactogenic effect of risperidone.

[Use of intravascular laser irradiation of blood in the treatment of drug-resistant forms of schizophrenia]. / Primenenie vnutrisosudistogo lazernogo oblucheniia krovi pri lechenii terapevticheski rezistentnykh form shizofrenii.

Overall 62 schizophrenic patients resistant to all forms of treatment were examined for the clinical efficacy of the treatment method on the basis of intravascular laser blood irradiation. A detailed description of the method, equipment, optimal doses, and the degree of effect in different psychopathological syndromes are provided. The best results were obtained in cases where the depressive paranoid symptomatology was predominant. The authors give recommendations for practical use of laser therapy under the conditions of the psychiatric hospital, discuss its action mechanism.

Densidad de probables receptores dopaminérgicos en los linfocitos de los pacientes con esquizofrenia paranoide: resultados preliminares / Densitx of probable dopaminergic receptors in lymphocytes of patients with paranoid schizophrenia: preliminary results

Los estudios con tomografía por emisión de positores y los estudios postmortem indican que por lo menos un grupo de pacientes esquizofrénicos experimentan un aumento en la densidad de los receptores para la dopamina (tipo D2) a nivel central. Recientemente Bondy y Cols. (3) informaron que este incremento también podría observarse en los linfocitos de estos pacientes y que, además, pudiera ser un marcador de vulnerabilidad, es decir, una característica que se hereda junto con la propensión a padecer la enfermedad. Es evidente que, de ser esto cierto, constituiría un hallazgos trascedental en el estudio de tan devastaddora enfermedad. Sin embargo, la evidencia sobre los sitios de un unión dopaminérgicos en los linfocitos es muy controvertida ya que algunos autores (12) no han podido demostrar la unión específica de ligandos dopaminérgicos en estas células, por lo que en este trabajo estudiamos la unión de 3H-espiperona en linfocitos de pacientes esquizofrénicos y en voluntarios sanos

[Free amino acids and the total middle molecule fraction of the blood serum in patients with continuously progressive paranoid schizophrenia undergoing treatment]. / Svobodnye aminokisloty i obshchaia fraktsiia srednikh molekul syvorotki krovi bol'nykh nepreryvno protekaiushchei paranoidnoi shizofreniei, nakhodiashchikhsia na lechenii.

The authors have investigated the levels of free amino acids and of the total fraction of medium molecules in the blood serum of patients with the paranoid form of continuously progressive schizophrenia. It has been demonstrated that these parameters are different in clinically normal individuals versus schizophrenics. The concentrations of free amino acids were the highest in people aged 40 to 50 years (Cys, Ala, Lys, Asp, Thr, Tyr, Try, Val, Leu, Ile) being considerably lower in individuals aged 50 to 60 years (Cys, Ala, Tyr) and over 60 years (Lys, His, Asp, Tyr, Try) which corresponds to the highest activity of the process in patients aged 40 to 50 years and its stabilization in older age.

[Middle-molecule spectrum of the blood serum in patients with a continuously progressive paranoid form of schizophrenia undergoing treatment]. / Srednemolekuliarnyi spektr syvorotki krovi bol'nykh nepreryvno progredientnoi paranoidnoi formoi shizofreniei, nakhodiashchikhsia na lechenii.

Screening and gel filtration on Sephadex G-15 (Pharmacia, Sweden) were used to study mean molecular (MM) components (the level of total fraction and spectrum) in the serum of patients suffering from continuously progressing paranoid schizophrenia. The findings evidenced elevated level of the fraction and rearranged spectrum of the components. MM components 5 significant increase and peaks I decrease registered in the study may play a role in pathogenesis of the disease and underlie the development of its productive symptoms.