Guenter Hetzel

Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF.

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S100B serum levels and long-term improvement of Negative symptoms in patients with schizophrenia

S100B, a calcium-binding protein produced by astroglial cells, mediates paracrine and autocrine effects on neurons and glial cells. It regulates the balance between proliferation and differentiation in neurons and glial cells by affecting protective and apoptotic mechanisms. Post-mortem studies have demonstrated a deficit in synapses and dendrites in brains of schizophrenics. Recent studies have shown increased S100B levels in medicated acutely psychotic schizophrenic patients as well as unmedicated or drug naive schizophrenics. One study reported a positive correlation between negative symptoms and S100B. S100B serum levels (quantitative immunoassay) and psychopathology (Positive and Negative Syndrome Scale, PANSS) were examined upon study admission and after 12 and 24 weeks of standardized treatment in 98 chronic schizophrenic patients with primarily negative symptoms. Compared to age- and sex-matched healthy controls, the schizophrenic patients showed significantly increased S100B concentrations upon admission and after 12 and 24 weeks of treatment. High PANSS negative scores were correlated with high S100B levels. Regression analysis comparing psychopathology subscales and S100B identified negative symptomatology as the predicting factor for S100B. S100B is not just elevated during acute stages of disease since it remains elevated for at least 6 months following an acute exacerbation. With regard to psychopathology, negative symptomatology appears to be the predicting factor for the absolute S100B concentration. This might indicate that S100B in schizophrenic patients either promotes apoptotic mechanisms by itself or is released from astrocytes as part of an attempt to repair a degenerative or destructive process.

Oral citalopram and reboxetine challenge tests before and after selective antidepressant treatment

Citalopram Lv. leads to dose-related increases in plasma prolactin levels in healthy subjects (Seifritz et al., 1996; Attenburrow et al., 2001), but not in depressed patients (Kapitany et al., 1999), probably due to serotonergic hypofunction in depression. In healthy subjects plasma prolactin levels are enhanced 2 h after the central noradrenergic system is activated by an oral reboxetine challenge (Schule et al., 1999). We wanted to test whether simple oral neuroendocrine challenge tests (prolactin responsiveness after citalopram or reboxetine) detect changes in monoaminergic function after selective antidepressant treatment. Twenty-four depressive in-patients were treated for 4 weeks with either citalopram or reboxetine in a prospective, randomised study. Before and after this selective treatment oral reboxetine or citalopram challenge tests were performed. The study was carried out according to the Tokyo revision of the Helsinki Declaration after approval by the local Ethics Committee. Thirty-six depressive in-patients were included in the study after giving their written informed consent. DSM-IV diagnosis of unipolar depression was assessed via DIA-X (Wittchen et al., 1997). Patients were assigned randomly to receive either reboxetine (n=17) or citalopram (n=19). Patients who were not physically healthy, needed further medication, had a history of endocrine disorders, were pregnant or were suffering from alcohol or drug abuse were not included in the study. Three days before the tests started, patients were treated exclusively with diazepam (for agitation) and zaleplon (for insomnia) in order to wash out previous antidepressant medication. At 08:00, blood samples for basal prolactin measurement were drawn. At 08:05, the patients randomised in the reboxetine-group received 4 mg of reboxetine as a single oral dose and at 10:00 blood samples for prolactin measurement were drawn. At 08:05, the patients randomised in the citalopram-group received 20 mg of citalopram as a single oral dose and at 12:00 blood samples for prolactin measurement were drawn. All patients were then treated for 4 weeks with the same drug used in the challenge test. Only diazepam and zaleplon were allowed as additional medications. After receiving 4 mg of reboxetine in the morning for the first four days, the reboxetine-group received 8 mg of reboxetine per day. After receiving 20 mg of citalopram in the morning for the first four days, the citalopram-group received 40 mg of citalopram per day. After 4 weeks of treatment the challenge procedure was repeated, on day 29 patients only received stimulation medication (4 mg reboxetine or 20 mg citalopram). Most patients showed blunted neuroendocrine challenge tests with decreases rather than increases of prolactin levels over time due to the strength of the underlying circadian rhythm of this hormone: data are shown as increases of prolactin above basal values measured at 08:00 this is the reason why they reveal negative values on the whole. A 2 2 analysis of variance was conducted on prolactin responsiveness with medication (reboxetine vs. citalopram) as the between-group independent variable and time (day 1 vs. day 29) as the repeated-measures independent variable. The interaction between group time was significant (F=13.782, P<0.001). A post-hoc test (Tukey HSD) shows that prolactin responsiveness in the reboxetine challenge test after a 4-week reboxetine treatment did not significantly change compared to before treatment (day 1: 2.76 ng/ml 3.35 ng/ml; day 29: 5.32 ng/ml 4.51 ng/ml;P=0.288; n=11), but prolactin responsiveness in the citalopram challenge test after a 4-week citalopram treatment is

Basal Prolactin Values Correlate with Response to Reboxetine Treatment in Major Depression, but Not with Response to Citalopram

Little is known about variables that might predict outcome in major depression. Recently, basal prolactin values (BPV) have been suggested to predict response to treatment with tricyclic antidepressive drugs. In order to examine whether BPV predict response to selective mono-aminergic therapy, 24 in-patients with major depression were treated in a single-masked, randomised study using the most selective noradrenergic or serotonergic reuptake inhibitors available for antidepressant treatment, i.e. reboxetine and citalopram. A significant correlation between BPV and treatment response to reboxetine was found, but not between BPV and response to citalopram. As BPV are influenced by noradrenergic activity, it can be hypothesized that depressed patients with comparatively high BPV have a relatively high noradrenergic function. This might explain why in our study depressed patients with the highest BPV responded strongest to selective noradrenergic treatment with reboxetine. As measurement of BPV is simple, further studies are suggested to examine the possible clinical value of the link between prolactin, noradrenergic function in major depression and treatment response.

A case of non-SIADH-induced hyponatremia in depression after treatment with reboxetine

Hyponatremia is a well-known side effect of antidepressant treatment with serotonin reuptake inhibitors (SSRI) or combined serotonin and noradrenaline reuptake inhibitors (SNRI), and is linked to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in most cases. In contrast, only very few data are available on hyponatremia following treatment with selective noradrenalin reuptake inhibitors (NaRI). In this report, we describe the case of a patient who developed severe hyponatremia after treatment with reboxetine. However, extensive laboratory testing did not reveal inappropriate secretion of ADH, suggesting that SIADH did not account for hyponatremia in our case. Proposing further examination of the underlying pathomechanism of hyponatremia as a side effect of NaRIs, we discuss the importance of careful monitoring of serum sodium levels in patients treated with NaRIs.