Serum S100B and schizophrenia
With respect to research in schizophrenia and S100B, most of the studies were carried out in serum. In general, authors have found increased S100B levels in patients (chronic schizophrenia, acute relapse and in first-episode psychosis) compared to healthy controls.[6, 7, 16, 18, 31, 49-51] In plasma, the results differ from that of serum levels. Gattaz et al. compared plasma S100B concentrations of 23 schizophrenic patients treated with antipsychotics (16 of them with clozapine) with plasma S100B levels of healthy controls, finding lower levels of plasma S100B concentrations in patients than in the healthy control group. The decrease of S100B is also supported by another study, where astrocytic C6 cells and oligodendrocytic OLN-93 cells cultured with haloperidol and clozapine decreased the release of S100B; however, the decreased levels of S100B reported by Gattaz et al. should be interpreted with caution because the concentration of S100B was measured in plasma (with citrate as anticoagulant) and it has been reported that plasma S100B concentrations are about 10 times higher than those measured in serum.
In 2001, in a study with 20 schizophrenic patients without antipsychotic treatment, the serum S100B concentrations found in the patient group were higher than in the healthy control group. The authors did not find correlations between S100B levels and the Positive and Negative Syndrome Scale (PANSS) scale or duration of the disease.
In another study with schizophrenics treated for 3 weeks (16 on antipsychotic treatment and 14 untreated), S100B was higher in the treated group compared to untreated and controls. Also, in those schizophrenics with predominantly residual or negative symptoms, S100B levels were higher. Rothermundt et al. carried out a longitudinal study of 26 patients with untreated schizophrenia, where S100B was measured at baseline and after 6 weeks of antipsychotic treatment. At baseline, S100B levels were higher in patients than in healthy controls, but at week 6 this difference was not present; however, in a subgroup of patients with persistent negative symptoms, S100B concentrations remained high. One possible explanation may be that antipsychotics increase the levels of S100B in the first weeks of treatment and then S100B remains elevated only in those patients with predominantly negative symptoms. Studies with longer follow-up periods are required.
Another longitudinal study with 98 schizophrenic patients with predominantly negative symptoms over 24 weeks of treatment with risperidone or flupenthixol was published in 2004. It was concluded that negative symptoms predict the concentration of S100B in serum, that is, those with higher levels of S100B had more persistent negative symptoms.
Twenty-three healthy controls and 41 elderly chronic schizophrenics (14 were on haloperidol or typical antipsychotics, 15 on clozapine and eight on haloperidol or clozapine combined with typical antipsychotics) were compared in another study. It was found that there were higher levels of serum S100B in schizophrenic patients and there was a negative correlation between the Scale for the Assessment of Negative Symptoms (SANS) score and S100B. Also, S100B correlated positively with age in schizophrenic patients (but not in controls). These results disagree with previous studies in younger patients where there was a positive correlation between the PANSS negative subscale and serum S100B levels.[7, 16, 55] This is the only study that has found S100B sex differences between men and women in schizophrenic patients, with women having lower levels of S100B than men, while most of the studies have not reported this difference.[7, 33, 49, 55, 56]
In 2007, Sarandol et al. reported that serum S100B levels were higher in patients with negative symptoms than those with positive symptoms and the controls. These levels were significantly reduced after 6 weeks of antipsychotic treatment.
In 2009, a relapsed schizophrenic group was compared to healthy controls. S100B analytical monitoring was performed weekly from admission to discharge. They also measured the neuron-specific enolase (NSE), which is found in the cytoplasm of neuronal cells and is not secreted actively, thus, it may be considered as a marker of neuronal destruction or brain damage. Higher S100B levels were found in the schizophrenic group compared to controls, with significant differences for NSE. The same group carried out a meta-analysis of published studies from 1970 to 2007 (12 studies in total), concluding that S100B in schizophrenics was higher than in controls, with no effect of antipsychotic treatment on S100B concentrations. The authors suggest that S100B levels are increased by active secretion of astrocytes and BBB dysfunction in schizophrenia.
Chronic schizophrenics treated with clozapine or typical antipsychotics have also been compared to healthy subjects. Higher levels of serum S100B were found in the schizophrenic group. There were no differences in S100B levels between the types of antipsychotic. There was no correlation between PANSS total score and S100B levels.
Recently, the role of the soluble receptor for advanced glycation end-products (sRAGE) in schizophrenia has become the object of research. RAGE is the main S100B receptor, which is located in neurons, glia, T cells and endothelial cells. RAGE is also the main receptor for amphotericin and β-amyloid, and contributes to the development of atherosclerosis, rheumatoid arthritis, diabetes and Alzheimer's disease. sRAGE counteracts the action of RAGE. Steiner et al. investigated whether sRAGE increased in the recovery period of the paranoid schizophrenic patients and contributed to the normalization of S100B levels. They concluded that sRAGE increased over the 6-week follow up and that it negatively correlates to S100B levels. Therefore, the authors consider sRAGE as a reducing factor of S100B levels and suggest that in the near future, sRAGE may be considered for new treatment strategies for schizophrenia.
A comparison of the serum S100B levels in untreated recent-onset psychotics, chronic schizophrenics under treatment and healthy controls showed that the serum S100B levels in the untreated recent-onset psychotics were higher than in the chronic treated schizophrenics. The authors suggested that low levels of S100B in treated patients are due to the decrease of neurodegeneration caused by antipsychotics. No differences in S100B levels between the different types of antipsychotic drugs, smoking, age or sex were found.
This research group also found elevated serum S100B concentrations in a sample of schizophrenic patients with tardive dyskinesia. They link this phenomenon to neurodegeneration because patients with tardive dyskinesia had higher levels of S100B than both the schizophrenics without dyskinesia and the healthy controls.
Data about psychopathology and S100B concentrations are controversial. A positive correlation between the third Brief Psychiatric Rating Scale (BPRS) item score (thought disturbance) and the concentration of S100B and a positive correlation between total PANSS scores and S100B levels have been reported. The same group reported a negative correlation between S100B levels and PANSS negative scores. The patients of this study were selected with prominent negative symptoms, so this bias may explain the results. Also, no correlations between S100B levels and PANSS total, positive, negative and general scores have been reported.[49, 58] In our opinion, biases in the selection of the patients, for example those with prominent negative symptoms, and the use of different scales to measure psychopathology (BPRS, PANSS, SANS, etc.) are partly responsible for the contradictory results.
In vitro studies have reported that both haloperidol and clozapine decrease the release of S100B by astrocytic and oligodendrocytic cells; however, studies carried out on schizophrenic patients are not so clear. Increased[49, 59] and decreased S100B levels have been reported. Regarding the distinction between typical and atypical antipsychotics, there do not seem to be differences between atypical and typical antipsychotics; indeed some authors have reported that patients present higher levels of S100B than controls, independently of whether they were treated with typical or atypical antipsychotics. To have a definitive opinion on this subject, studies with bigger samples of patients treated with only one antipsychotic should be carried out. In a clinical setting, however, monotherapy is not the usual rule and this is the reason why different antipsychotics are converted into chlorpromazine-equivalent doses so that there are enough patients to compare. As a consequence of this, specific details, such as the differences between typical and atypical antipsychotics, are lost.
There is agreement with respect to the effect of illness duration and age of illness onset on S100B levels. It has been reported that neither are related to S100B concentrations.[16, 21, 33, 49, 52, 55, 56, 61] There is only one exception, which reported a negative correlation between illness duration and S100B levels. We do not have an explanation for this result.
No sex differences in S100B levels have been reported in patients with schizophrenia.[7, 33, 49, 55, 56] Only one paper has reported that schizophrenic men had higher levels of S100B than schizophrenic women.
In healthy subjects, S100B plasma levels have been reported as not correlated to age[23, 49, 50] as well as having a positive correlation with age. In patients with schizophrenia, no link between age and serum levels of S100B has been reported,[7, 16, 21, 49, 50, 55, 56, 61] although others have found a positive correlation between age and S100B serum levels.
Other variables that may affect S100B concentrations are body mass index and nutrition. It is noticeable that those variables are not routinely included in the S100B schizophrenia protocol studies. A positive and an absence of correlation have been reported in healthy subjects and patients with several pathologies. Due to the scarcity of publications on this topic, we believe that more research is needed before reaching a definitive conclusion. It has been reported that chronic starvation (anorexia nervosa) is related with low S100B levels and a posterior weight gain is characterized by a recovery of the S100B levels; however, no differences in S100B concentrations have been reported between subjects following a normal diet and subjects following a diet supplemented with mixed-grain. More research on the relation between nutrition and S100B levels in both healthy and diseased subjects is needed.
Adipocytes are an extracerebral source of S100B, therefore the increase in serum S100B could be due to an increase or a dysfunction of adipose tissue. S100B secretion by adipocytes is reduced by insulin and activated by physiological factors, such as stress, cathecolamines and fasting. In healthy subjects, a positive correlation between body mass index and S100B levels has been reported. Patients with schizophrenia have an increased risk for type 2 diabetes mellitus and metabolic syndrome, with increased insulin resistance (mediated in the brain) and therefore they present an increase of S100B levels. It is not clear if the S100B protein may be a marker of metabolic syndrome in schizophrenia.[62, 69] Therefore, obesity and insulin resistance may affect S100B serum levels.
It should be pointed out that the lack of agreement between different studies may be due to methodological errors. The type of anticoagulant with which blood is treated, such as sodium heparin, sodium citrate and ethylenediaminetetraacetic acid (EDTA), can alter S100B levels. Tort et al. compared S100B levels of the same subjects with and without anticoagulant. They found a positive correlation between serum S100B and S100B in plasma collected with heparin. They obtained an increase of S100B in the samples of heparin and citrate, while no differences with those of EDTA and serum. Since citrate and EDTA are calcium chelators, they have more interference with the analytical results; on the other hand, heparin always showed a strong positive correlation with serum. Thus, if blood needs to be anticoagulated, heparin is preferred. Ling et al. heparinized their plasma samples before measuring S100B levels. They reported a positive correlation of S100B plasma levels and PANSS total score at admission, and this correlation mainly existed between S100B levels and the PANSS negative subscore.
Circadian rhythmicity should also be taken into consideration. Our group carried out a study with 43 schizophrenic patients admitted to a psychiatric ward because of an acute relapse. At admission, S100B serum daytime levels were higher than night-time levels, and this pattern disappeared when the patient was clinically stabilized before discharge.
Regarding seasonal variation, after examining blood samples from 33 healthy subjects, serum S100B levels were significantly higher in the samples drawn in summer when compared to winter (results from our own research pending publication).
Recent research links the neuroinflammation hypothesis of schizophrenia with microglia. S100B acts as a cytokine after secretion from glial cells, CD8 + lymphocytes and natural killer (NK) cells, activating monocytes and microglial cells.[72-74] It is known that activated microglia release pro-inflammatory cytokines and free radicals, and these cause neuronal degeneration and decrease neurogenesis. Recent results of Bianchi et al.[72, 73] suggest that S100B may participate in the pathophysiology of brain inflammatory disorders via RAGE regulation with activation and migration of microglia. Furthermore, S100B upregulates cyclo-oxygenase-2 expression in microglia in a RAGE-dependent manner. The minimum levels of RAGE that are necessary for the S100B to exert a toxic or neuroprotective effect are still unknown; however, according to Steiner et al., in schizophrenic patients, S100B + NK cell counts are correlated with the free cortisol index (marker for stress axis activity) but not with the S100B serum concentrations. These results suggest that NK are probably not a major source of S100B in the blood of schizophrenia patients.