The Effect of Ibuprofen on Cytokine Production by Mononuclear Cells from Schizophrenic Patients.

The existence of a restrained inflammatory state in schizophrenic individuals posed the question whether anti-inflammatory drugs may exert antipsychotic effects. Therefore, the effect of ibuprofen (IB) on cytokine production by human peripheral blood mononuclear cells (PBMC) from schizophrenic patients was examined and compared to that of healthy subjects. PBMC from 25 schizophrenic patients and 24 healthy volunteers were incubated for 24 h with lipopolysaccharide (LPS) in the absence or presence of various concentrations of IB. The levels of IL-1ß, IL-6, TNF-α, IL-10 and IL-1ra in the supernatants were tested applying ELISA kits. The secretion of TNF-α by cells from schizophrenic patients was significantly lower compared with controls. IB caused stimulation of TNF-α and IL-6 production by cells of the two groups and enhanced IL-1ß secretion by cells from schizophrenic patients. IB inhibited IL-1ra and IL-10 generation by cells from the two groups. Without IB, IL-1ra secretion was negatively correlated with the disease severity, while 200 µg/ml of IB positively correlated with the PANSS total score. IL-10 production was positively correlated with the PANSS positive subscale score both in the absence or presence of IB. The findings suggest that the effect of IB on the production of inflammatory cytokines may benefit the health of schizophrenic patients.

Difference in inflammatory cytokine production by mononuclear cells from obese and non-obese schizophrenic patients.

OBJECTIVE: Schizophrenic patients have an increased risk for obesity compared with the general population. Evidence suggests the existence of an inflammatory process in the etiology of both obesity and schizophrenia. Our study compares in vitro secretion of inflammatory cytokines by peripheral blood mononuclear cells (PBMC) obtained from obese and non-obese schizophrenic patients. METHOD: Mononuclear cells were isolated from 20 obese (BMI >27) and 20 non-obese (BMI <24) schizophrenic in-patients. The levels of TNF-α, IL-1ß, IL-6, IL-1ra, IL-10 or IL-2 and IFN-γ in the supernatants of stimulated PBMC, as well as leptin and adiponectin serum values were evaluated. RESULTS: Peripheral blood mononuclear cells from patients in the obese group showed a significantly increased TNF-α and IL-1ß production, whereas the release of IL-1ra was decreased as compared with the non-obese group. In the obese group, the serum concentration of leptin was significantly higher and that of adiponectin was significantly lower. The results of the remaining cytokines did not differ between the two groups. CONCLUSION: Our study indicates the existence of a difference between obese and non-obese schizophrenic subjects as for inflammatory cytokine production and serum leptin and adiponectin levels, suggesting a 'subclinical inflammatory state' in obese schizophrenic patients that may contribute to a predisposition to inflammation and infections.

Autoantibodies to DNA in multicase families with schizophrenia.

In an attempt to define the autoimmune status of members of multicase families with schizophrenia, sera of both patients and healthy relatives from 28 such cases were tested for antinuclear antibodies, anti-double-stranded DNA, and anti-single-stranded DNA autoantibodies. These autoantibodies were significantly more frequent in both schizophrenic patients and healthy relatives than in normal subjects. Immunoglobulin (Ig) M anti-DNA antibodies were more common in patients, whereas in healthy relatives, IgG anti-DNA antibodies were more common. No significant differences were found between schizophrenic patients and their healthy relatives. The data indicate that an autoimmune process may be involved in the etiology of a subset of patients with schizophrenia.

First night effect in depression: new data and a new approach.

Polysomnography was performed in 20 depressed patients and 8 normal controls for 2 consecutive nights. A subset of patients had 3 consecutive nights. Patients were assigned to groups according to the presence (group I) or absence (group II) of a first night effect (REM sleep latency on the first night in the laboratory was at least 30 min longer than on the second night). The groups were equivalent with regard to gender distribution, age, and severity of depression. In group I, REM sleep latency on nights 2 and 3 was significantly shorter than in group II. REM sleep percentage on the second night in group I was increased compared to the first night. A shift of REM sleep to the first cycle was prominent on the first night only in patients with a first night effect. On average, delta sleep was preserved in group I compared to group II. We suggest that the first night effect reflects a physiological system with greater capacity to respond adaptively and to preserve homeostasis when confronted with environmental stressors.

Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia.

OBJECTIVE: The authors examined the efficacy, tolerability, and safety of ondansetron, a selective serotonin 3 receptor antagonist, in patients with tardive dyskinesia. METHOD: Twenty patients with schizophrenia who had neuroleptic-induced tardive dyskinesia were given 12 mg/day of ondansetron for 12 weeks in an open-label study. RESULTS: Administration of ondansetron resulted in a statistically significant improvement in tardive dyskinesia and psychotic symptoms. CONCLUSIONS: Ondansetron may be an effective and safe therapy to control tardive dyskinesia and psychosis in patients with schizophrenia.

Antibodies to neuroblastoma cell line proteins in patients with schizophrenia.

The presence of antibodies against neural antigens was investigated in the serum of patients with schizophrenia, major depression and normal controls. Different immunological abnormalities, humoral and cellular, were reported in schizophrenia and major depression. The pathogenesis of schizophrenia is multifactorial. An autoimmune mechanism was suggested as a possible factor. We tested the serum of 26 patients with schizophrenia, eight patients with major depression and 22 normal controls. The serum samples were tested for antibody binding to protein extracts of IMR-32 neuroblastma cell line using Western blot analysis. Immunoglobulins of eight patients with schizophrenia (30.71%) reacted with a protein of 80-85 kDa. Serum samples from subjects of other groups did not react with this protein. Sera of all patients with major depression but one, and all normal controls reacted with HSP 60 kDa to different extent. This is an apparent discrepancy with the findings of Kilidireas et al. [Kilidireas, K., Latov, N., Strauss, D.H., Gorig, A.D., Hashim, G.A., Gorman, J.M., Sadig, S.A., 1992. Antibodies to the human 60 kDa heat shock protein in patients with schizophrenia. Lancet 340, 569-572.] who demonstrated the presence of antibodies against HSP 60 kDa in 44% of patients with schizophrenia tested and 8% of normal subjects. HSP 60 kDa is an antigen of many pathogens and antibodies against it might be a result of an infection and cannot be a good indicator for an autoimmune process. The presence of antibodies against a protein of 80-85 kDa should be investigated as a possible specific indicator.

Platelet autoantibodies in dementia and schizophrenia. Possible implication for mental disorders.

Platelets isolated from blood of demented and schizophrenic patients were found to bear surface antibodies at a considerably higher titer than those found on platelets from normal age-matched groups or patients with affective disorders. The platelet count in demented and schizophrenic patients correlated inversely with the level of the platelet associated antibodies (PAA) which suggested an autoimmune route of opsonization. In most individual cases of dementia or schizophrenia PAA and platelet count were found to oscillate with time between high PAA-low platelet number and low PAA-high platelet number in approximately inverse correlation. PAA isolated from demented patients were found to cross-react with platelets from normals and with brain tissue from rats. Furthermore, molecular weights of specific brain antigens were identified by binding to PAA. These observations support the possibility that PAA might be implicated in the etiology of some mental dysfunctions associated with dementia and schizophrenia.

Increased interleukin-1 and interleukin-3 like activity in schizophrenic patients.

1. The interleukins play an important role in the development and maintenance of the immune system 2. Decreased cell mediated immunity measures were found in schizophrenic patients. 3. The purpose of the present study was to study the spontaneous production of interleukin-1 (IL-1) and interleukin-3 like activity (IL-3-LA) by human mononuclear cells from schizophrenic patients in comparison to healthy individuals. 4. Interleukin-1 was increased significant by schizophrenic patients as compared to controls. 5. Interleukin-3 like activity was slightly elevated in schizophrenic patients as compared to controls. 6. These findings support the hypothesis of an autoimmune dysfunction in some schizophrenic patients.

Sialic acid in platelets of schizophrenic patients.

1. Nerve cell membrane sialic acid is involved in the activity of nervous tissue by its capacity to bind Ca ions and positively charged biogenic amines. 2. Blood platelets may serve as a model for amine-storing neurons. 3. The purpose of the present study was to determine the sialic acid content of platelets of schizophrenic patients in view of reports showing a reduced serotonin uptake by their platelets. 4. To this end platelets were isolated from the blood of 26 schizophrenic patients (13 males and 13 females) of various diagnostic subtypes and from 21 healthy subjects, and sialic acid was determined after hydrolysis at 80 degrees for 1 h in 0.1 NHCl. 5. The results showed significantly lower contents of sialic acid in the patients as compared to controls calculated both per 10(8) cells and per mg protein (18% and 25% lower, respectively) and appear to be in line with the reduced serotonin uptake in their cells in schizophrenia. 6. There were no appreciable differences between sexes and between the various subtypes of this disease.

Increased anti-Sm antibodies in schizophrenic patients and their families.

1. Autoantibodies in the Sm complex have become a useful serologic aid in the diagnosis of systemic lupus erythematosus (SLE) and have rarely been observed in other diseases. 2. A subset of SLE patients have a variety of psychiatric abnormalities, including schizophrenia. 3. The authors have recently observed that schizophrenic patients have a high incidence of autoantibodies suggesting that autoimmune phenomena may play a role in the pathogenesis of this disease. 4. In the present study the authors investigated multicase families with schizophrenia for the presence of anti-Sm antibodies and showed that these autoantibodies are elevated both in patients and in their healthy relatives. 5. An autoimmune process may be involved in the pathology of schizophrenia.

An open study of fluvoxamine augmentation of neuroleptics in schizophrenia with obsessive and compulsive symptoms.

Patients whose schizophrenia is characterized by marked obsessive-compulsive features can be difficult to treat successfully and often require a combination treatment. The aim of this open-label study was to evaluate the efficacy and tolerability of an addition of fluvoxamine--a selective serotonin reuptake inhibitor (SSRI)--to standard neuroleptics in treatment of obsessive-compulsive (OC) symptomatology in patients with schizophrenia. Sixteen patients with schizophrenia were treated with conventional neuroleptics and fluvoxamine in doses of 100-200 mg/d for 8 weeks. The patients were assessed with use of the Brief Psychiatric Rating Scale (BPRS) and the Yale Brown Obsessive-Compulsive Scale (YBOCS) at baseline and endpoint. Results included considerable reduction in BPRS (39.4%) and Y-BOCS (32.9%) scores. None of the patients showed an acute exacerbation during the whole study period. Side effects were clinically insignificant. This open-label trial supports previous suggestions that coadministration of SSRIs and neuroleptics in patients with schizophrenia with OC symptoms is associated with robust improvements of these symptoms. Therefore, the use of SSRIs in patients with schizophrenia with OC symptomatology may be warranted and safe.

The effect of chlorpromazine and haloperidol on DNA transcription.

The ability of human cells to repair DNA damage can be indirectly assessed by measuring transcriptional activity relating to active genes, a process referred to as RNA synthesis. This study was carried out to investigate the effects of chlorpromazine and haloperidol on the transcriptional activity of actively transcribed genes as an expression of DNA damage and repair. Three cultured human fibroblast lines were used: two were "normal" in previous RNA recovery testings and one was abnormally sensitive to UV irradiation. In the "normal" line, recovery of RNA synthesis occurred within 1 hour of UV after exposure to three concentrations of chlorpromazine (125, 250 and 500 ng/ml) and haloperidol (5, 10 and 20 ng/ml). Following treatment with the same concentrations of chlorpromazine and haloperidol, the UV-sensitive cell line showed markedly depressed recovery of RNA synthesis at 1 and 4 hours. Complete recovery was not reached even after 24 hours. Our results suggest that neuroleptics widely used in clinical practice adversely affect cell lines that are sensitive to DNA-damaging agents.

REM sleep in depressed patients: different attempts to achieve adaptation.

Twenty-seven depressed patients and 10 healthy subjects were investigated in the sleep laboratory during two to three consecutive nights. Eleven of the 27 patients demonstrated the "first night effect" (group I) and 11 other patients demonstrated a clear absence of the "first night effect" (group II). Five of the 27 depressed patients were omitted from the study because they did not fit criteria for first night effect. The 10 healthy controls demonstrated a first night effect. In group I, the duration of the first rapid eye movement (REM) sleep episode was increased on the first night and on the second night the REM sleep latency was decreased, whereas REM sleep duration and eye movement (EM) density was increased. The number of the short sleep cycles (less than 40 minutes) was greater in group I versus group II and the percentage of slow-wave sleep (SWS) was also higher in group I. In depressed patients with the "first night effect" the enhanced REM sleep requirement is satisfied not only by an increased REM sleep duration but also by the improved REM sleep quality that is crucial for adaptation. The adaptive role of the increased first REM period and the increased EM density in this period is very limited.

Superoxide anion production by neutrophils derived from peripheral blood of schizophrenic patients.

Evidence indicates that excess free radicals formation may occur in patients with schizophrenia. A study comparing the production of superoxide anion by peripheral blood neutrophils of 29 schizophrenic patients with that of 17 healthy volunteers detected a significant statistical increase in superoxide anion production in schizophrenic patients compared to the healthy control group. Despite the fact that oxidative mechanisms may play a role in schizophrenia, further studies are needed to define their involvement. Such studies would shed light on the etiology and pathogenesis of schizophrenia and may lead to new therapeutic approaches using antioxidants, which might partially alleviate or prevent the symptoms of schizophrenia.

Increased olfactory sensitivity in first episode psychosis and the effect of neuroleptic treatment on olfactory sensitivity in schizophrenia.

Olfactory sensitivity to two odorants, isoamyl acetate and androstenone, was assessed in 19 male schizophrenic patients and 10 control subjects. Tests were performed during a drug-free period and 2-3 weeks after initiation of neuroleptic drug therapy. Olfactory sensitivity in schizophrenic patients was significantly impaired during the drug-free period and neuroleptic treatment further reduced olfactory sensitivity in these patients. The same olfactory tests were administered to 22 first-episode-psychosis patients, 12 first-episode-schizophrenia and 10 brief-psychotic-disorder patients, as well as to 20 age-matched control subjects. The first-episode-psychosis patients had significantly higher sensitivity to isoamyl acetate and to androstenone, but the incidence of anosmia to androstenone was not higher in the first episode patient group as compared to the control group. We conclude that olfactory dysfunction in schizophrenic patients, and possibly other forms of psychosis, is mainly due to long-term effects of commonly used neuroleptic drugs.

The relationship between subjective sleep estimation and objective sleep variables in depressed patients.

INTRODUCTION: To our knowledge there is no evidence in the literature about the relationship between subjective sleep estimation and objective sleep variables in depression. It is not known whether the subjective estimation of sleep quality and sleep duration is directly related to any objective sleep variable in depressed patients. METHODS: Thirty patients with major depression and 10 healthy subjects have been investigated in our sleep laboratory during 1 or 2 consecutive nights after 1 night for adaptation. Every subject, after final awakening in the laboratory, answered questions concerning the subjective feelings about sleep duration, number of awakenings and sleep depth. We compared the sleep estimation in both groups and calculated the correlation between objective and subjective sleep variables in depressed patients. RESULTS: The degree of a wrong sleep estimation in depressed patients is larger than in healthy subjects. Slow wave sleep (SWS) in depressed patients correlates positively with the subjective estimation of sleep duration. Eye movement density in REM sleep correlates with the subjective estimation of the number of awakenings. CONCLUSION: SWS in depression has a positive influence on the subjective feeling of sleep duration while phasic REM sleep activity has a negative influence.

Cancer morbidity in psychiatric patients: influence of lithium carbonate treatment.

The relationship between mental diseases and cancer development has been examined in a number of studies but the findings are still inconclusive and suffer from methodological problems. Studies conducted to examine the effect of lithium on malignant cells yielded inconsistent results. The study group included 609 patients treated by lithium carbonate and 2396 controls. A lower but non significant risk (RR = 0.79; CI = 0.17-3.60) to develop non-epithelial tumors was found among lithium carbonate treated psychiatric patients as compared to controls. A significantly (P = 0.05) inverse trend of cancer with lithium dose was observed. The risk of cancer development among each group of psychiatric patients was significantly lower than in the general population (RR = 0.68 for the lithium treated group versus 0.78 for controls). Mental patients have a lower cancer prevalence than the general population and lithium may have a protective effect.

A role for taste aversion learning in FLA-57 induced reductions of voluntary alcohol intake.

It has been proposed by Amit, Brown and colleagues that the reduction in voluntary alcohol intake observed after the administration of FLA-57 in rats can be attributed to decreased NE levels produced by FLA-57. Our studies investigated whether a conditioned taste aversion could better explain this phenomenon. In the key study, two groups of rats were injected with FLA-57 or Ringers before drinking alcohol for five days, while a third group was injected with FLA-57 before exposure to intragastrically intubated (untasted) alcohol in amounts identical to those in the tasted group. Results showed that only the FLA-57 group that tasted alcohol reduced subsequent voluntary alcohol intake. When a CTA was precluded, allowing only for an effect due to reduced NE, no reduction was observed. This suggests that FLA-57 reduces VAI, not via reduced NE levels, but by a conditioned taste aversion. A second study, utilizing saccharin instead of alcohol, generally supported this conclusion. While these results support a CTA explanation, it is possible that under other conditions FLA-57 might produce a central pharmacological effect.

Combined clozapine-lithium treatment for schizophrenia and schizoaffective disorder.

Three adolescent and two adult patients suffering from chronic excited psychoses (either schizophrenia or schizoaffective disorder) resistant to traditional neuroleptics and clozapine were treated with combined clozapine-lithium. Improvement was assessed with the Positive and Negative Symptoms Scale, the Brief Psychiatric Rating Scale and the Clinical Global Impressions, administered before and during combined clozapine-lithium treatment. All patients demonstrated a significant improvement with this combination. There was no occurrence of agranulocytosis, neuroleptic malignant syndrome or other clinically significant adverse effects.

A comparison of two modalities of cognitive therapy (individual and marital) in treating depression.

Historically, depression was explained and treated intrapsychically and/or biochemically. In the 1970s theoretical propositions and treatment applications began to appear that offered that depression should be viewed cognitively (Beck 1963, 1974; Beck et al. 1979) or interpersonally (Coyne 1976a, 1976b; Klerman et al. 1984). Simultaneously, though more sporadically, marital interventions started to attract interest (Feldman 1976; Friedman 1975). The cognitive and interpersonal trends of thinking stimulated researchers to investigate the efficacy of these therapeutic modalities and to compare them with each other. Interest in these two treatments peaked with the publication of the study that emerged from the National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program (Elkin et al. 1989). This well-known research found that the two psychotherapies were similarly effective, but that the interpersonal approach was slightly more successful with more severely depressed patients.