Nela Pivac

Platelet serotonin, plasma cortisol, and dexamethasone suppression test in Schizophrenic patients

BACKGROUND Serotonin (5-HT) regulates hypothalamic-pituitary-adrenal (HPA) axis activity. Abnormal response to the dexamethasone suppression test (DST) and altered platelet 5-HT concentration have been shown in some schizophrenic patients. METHODS Platelet 5-HT and plasma cortisol concentrations were determined simultaneously in 86 male schizophrenic patients before and after DST. Basal plasma cortisol and platelet 5-HT levels were also determined in 69 healthy male persons. RESULTS Schizophrenic patients had higher plasma cortisol and platelet 5-HT concentrations than healthy persons. An abnormal escape from dexamethasone suppression was observed in 50% of patients. In these patients predexamethasone cortisol and platelet 5-HT concentrations were higher than in patients with normal DST. CONCLUSIONS This study demonstrates that schizophrenic patients have the HPA axis dysregulation that could be connected with a disturbance in the 5-HT system.

The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide

BACKGROUND Brain-derived neurotrophic factor (BDNF) mediates neural plasticity, mood, different behaviours, and stress response. A functional BDNF polymorphism (BDNF Val66Met) was reported to influence the effects of stressful life events or childhood adversity on depression and suicidal behaviour in various psychopathologies. The study evaluated the association between BDNF Val66Met variants and suicide, committed with violent or non-violent methods, in victims with or without stressful childhood experience. METHODS BDNF Val66Met polymorphism was genotyped on 560DNA samples from 359 suicide victims and 201 control subjects collected on autopsy from unrelated Caucasian subjects and subdivided according to gender, method of suicide, and influence of childhood adversity. RESULTS A similar frequency of BDNF Val66Met variants was found between all included suicide victims and the control groups, and also between the male groups. The frequency of the combined Met/Met and Met/Val genotypes and the homozygous Val/Val genotype was significantly different between the female suicide victims and female controls, between the female suicide victims who used violent suicide methods and female controls, and between all included suicide victims with or without stressful life events. The combined Met/Met and Met/Val genotypes contributed to this significance. LIMITATION A small group of suicide victims with available data on childhood adversity was studied. CONCLUSIONS The combined Met/Met and Met/Val genotypes of the BDNF Val66Met variant could be the risk factor for violent suicide in female subjects and for suicide in victims exposed to childhood trauma. These results confirm a major role of BDNF in increased vulnerability to suicide.

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.

Platelet 5-HT concentrations and suicidal behaviour in recurrent major depression

Platelet 5-HT concentrations were determined in 84 male and 82 female psychotic and non-psychotic depressed inpatients with various degrees of suicidal behaviour, and in 175 healthy controls. Psychotic patients had higher platelet 5-HT concentrations than non-psychotic depressed patients and healthy controls. A sex difference, i.e., lower platelet 5-HT concentrations in females was found in healthy controls, depressed patients, non-psychotic patients and non-suicidal depressed patients. A negative relationship was shown between platelet 5-HT concentrations and suicidal behaviour. The lowest platelet 5-HT concentrations were associated with the most pronounced suicidal behaviour (with suicidal attempts and with the acts of suicide). The results suggest that the differences in platelet 5-HT concentrations found in depressed patients might be used as a biological marker for suicidal behaviour.

Dopamine beta‐hydroxylase (DBH) activity and ‐1021C/T polymorphism of DBH gene in combat‐related post‐traumatic stress disorder

The roles of dopamine (DA) and norepinephrine (NE) in posttraumatic stress disorder (PTSD) are unclear. The aim of the study was to determine plasma dopamine beta‐hydroxylase (DBH) activity and DBH‐1021C/T gene polymorphism in combat veterans with (N = 133) or without (N = 34) chronic PTSD. Similar frequencies in genotype or allele distribution were found between veterans with or without PTSD. War veterans with PTSD had lower DBH activity, associated with the DBH‐1021C/T variant in DBH genes, than veterans without PTSD. A significantly lower plasma DBH activity was found in combat veterans with PTSD carrying the CC genotype as compared to veterans without PTSD carrying the corresponding genotype. Since both groups were exposed to the same trauma, it is possible that a pre‐existing trait difference in regulation of NE function contributed to a differential vulnerability to develop PTSD, or that the regulation of DBH expression was different in response to trauma. The results suggest that that genotype‐controlled measurement of plasma DBH activity might be used as a potential biological marker of the response to trauma, and that further studies of DBH and other loci related to DA and NA in PTSD are warranted.

The role of the serotonergic system at the interface of aggression and suicide.

Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the multifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies. Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homoeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and identify new effective therapies for these conditions.

The effects of paroxetine and tianeptine on peripheral biochemical markers in major depression

Depression is related to the alterations of the central serotonergic system and some antidepressants achieve their therapeutic effects through alteration of serotonin (5-HT) (re)uptake. Peripheral biochemical markers, platelet and serum 5-HT concentrations, platelet monoamine oxidase (MAO) activity, plasma levels of cortisol and prolactin (PRL), were investigated in patients with major depression before and after 4 weeks of treatment with paroxetine (an inhibitor of 5-HT uptake) or tianeptine (a stimulator of 5-HT uptake). Study was open, single center and included female depressed patients, 21 treated with tianeptine (37.5 mg/day) and 15 treated with paroxetine (20 mg/day), and 11 drug-free healthy women (controls). Before treatment, depressed patients as a group had significantly higher serum 5-HT and cortisol concentrations than healthy controls. There were no differences in the other biochemical markers. Response to antidepressant treatment was estimated according to the 50% fall in the initial scores of Hamilton Depression Rating Scale (HAMD) after 4 weeks of treatment. Good therapeutic response was observed in 47% and 45% patients treated with paroxetine and tianeptine, respectively. Paroxetine treatment induced significant decrease in platelet 5-HT concentrations in both responders and nonresponders, while no alterations in platelet 5-HT values were found in tianeptine-treated patients. There was a subgroup of depressed patients in paroxetine-treated group with high pretreatment platelet 5-HT concentration and later poor therapeutic response to paroxetine treatment. Serum 5-HT values, platelet MAO activity or plasma cortisol or PRL levels were unchanged after both treatments. The results suggest that pretreatment platelet 5-HT levels, but not other peripheral biochemical markers, might predict therapeutic outcome at least in paroxetine-treated patients.

Effects of Sertraline Treatment on Plasma Cortisol, Prolactin and Thyroid Hormones in Female Depressed Patients

The aim of the study was to evaluate the effects of 4 and 24 weeks of sertraline treatment (average dose 42.5 mg/day) on plasma hormone levels in 15 female patients with major depression. Baseline levels of triiodothyronine (T3) were lower, while cortisol, prolactin (PRL), thyroid-stimulating hormone (TSH), and thyroxin (T4) levels did not differ from the values in 16 female controls. There was a positive correlation between the scores on the Montgomery-Asperg Depression Rating Scale and baseline cortisol levels. Treatment with sertraline for 4 weeks increased plasma cortisol levels, while 24 weeks of sertraline treatment increased plasma T3 levels in depressed patients. Neither 4, nor 24 weeks of sertraline treatment affected PRL, T4 and TSH levels in depressed patients. The data show different and time-dependent effects of sertraline treatment on plasma cortisol, PRL and thyroid hormones in female depressed patients.

Quetiapine treatment in an open trial in combat-related post-traumatic stress disorder with psychotic features

Patients with combat-related post-traumatic stress disorder (PTSD) with psychotic features frequently fail to respond to antidepressants. Previous research has shown that these patients improve significantly after monotherapy with two atypical antipsychotics, olanzapine and risperidone. This study investigated the clinical outcome of another atypical antipsychotic, quetiapine, in war veterans with combat-related PTSD with psychotic features. Male war veterans (n=53) with DSM-IV-diagnosed PTSD with psychotic symptoms completed 8 wk of in-patient treatment with quetiapine (25-400 mg/d). The reductions in the total and subscale scores on the Clinician-Administered PTSD Scale (CAPS), and the increase in the Clinical Global Impression - Improvement Scale (CGI-I) were the primary outcome measures, and reductions in the Positive and Negative Syndrome Scale (PANSS) were the secondary outcome measures. The CGI - Severity of Illness scale (CGI-S) was used to assess the global clinical improvement. Drug-Induced Extrapyramidal Symptoms scale recorded adverse effects. Two, 6 and 8 wk treatment with quetiapine significantly reduced total and the subscales scores on the CAPS, PANSS, and CGI-S scales, in patients with psychotic PTSD. The results indicate that 8 wk of monotherapy with quetiapine reduced the majority of the psychotic and PTSD symptoms in the patients. Our present and previous data suggest that treatment-resistant psychotic PTSD patients may improve after taking atypical antipsychotics.

Seasonal influence on platelet 5-HT levels in patients with recurrent major depression and schizophrenia

The influence of seasons on platelet serotonin (5-HT) concentration was determined in 88 unipolar depressed and 117 schizophrenic male inpatients, and 90 normal male controls. Platelet 5-HT concentrations showed moderate, but insignificant intragroup seasonal variations in healthy controls and in the groups of depressed (psychotic and nonpsychotic) and schizophrenic (positive and negative) patients. In spring, platelet 5-HT concentrations were higher in schizophrenic patients than in normal controls or in depressed patients, while in other seasons platelet 5-HT concentrations were not significantly different between the groups. Higher platelet 5-HT concentrations were detected in psychotic when compared to nonpsychotic depressed patients in summer, fall, and winter. Increased platelet 5-HT concentrations observed in schizophrenic patients with positive symptoms clearly separated these patients from patients with negative schizophrenia, especially in spring, summer, and fall. Our results indicate the necessity to match patients with regard to the season of the sampling, and to divide depressed and schizophrenic patients into subtypes.