Is MAO-B activity in platelets associated with the occurrence of suicidality and behavioural personality traits in depressed patients?

OBJECTIVE: Low platelet monoaminoxidase B (MAO-B) activity has been associated with various forms of impulsive behaviour and suicidality. The present study investigated the relationship between MAO-B activity in platelets and aspects of suicidality in depressed patients and controls. METHOD: In 87 patients with affective spectrum disorders (58% suffering from a major depressive episode - MDE) the potential association between platelet MAO-B activity and suicidality was examined. Fifty-nine of the patients had committed suicide attempt recently (SA -'suicide attempters'), 28 patients were acutely depressed without having shown suicidal thoughts or suicidal behaviour in the past (NA -'non-suicide attempters'). RESULTS: The SA and NA were comparable as to their diagnoses and general demographic and psychopathological parameters. MAO-B activity did not differ between SA and NA. No systematic correlations existed between MAO-B activity and any dimensions of suicidal behaviour or psychopathology. As a single finding only a weak positive association of higher MAO-B activity in SA with a fatal intention of the SA was observed. CONCLUSION: Our findings do not support a consistent association of platelet MAO-B activity and suicidal behaviour in general, but specific facts of suicidality might be associated.

Relationship between mirtazapine dose, plasma concentration, response, and side effects in clinical practice.

OBJECTIVE: The aim of this study was to evaluate the benefit of mirtazapine plasma concentration monitoring in a typical clinical setting. METHODS: The relationship between mirtazapine plasma concentration, dose, response, and side effects was studied in 65 inpatients presenting with a depressive episode according to ICD-10. Plasma concentrations, the 17-item Hamilton Depression Rating (HAMD), and the UKU side effect rating were performed weekly. A subgroup of 45 patients was evaluated for a concentration-response relationship. RESULTS: We found a low positive correlation between plasma concentration and dose. A low negative correlation between plasma concentration and increased duration of sleep was noted in the first week of mirtazapine treatment, but not during the entire observation time. Responders to mirtazapine treatment presented with higher plasma concentrations than non-responders, revealing a threshold concentration of 30 ng/mL. CONCLUSION: The mirtazapine dose is a weak predictor of mirtazapine plasma concentrations. Plasma concentration measurements may therefore be useful to adjust mirtazapine doses in non-responders with plasma concentrations below 30 ng/mL. Sedative effects appear temporary and require no plasma concentration control when standard doses are administered.

Pharmacokinetics of m-chlorophenylpiperazine after intravenous and oral administration in healthy male volunteers: implication for the pharmacodynamic profile.

INTRODUCTION: Serotonin plays an important role in psychiatric diseases, most notably in depression and anxiety. Seven different major serotonin receptor subtypes have been described. Receptor-selective agonists and antagonists have been searched for to find a suitable drug to test the in vivo receptor sensitivity. Different serotonin receptor subtypes take part in the control of neuroendocrine function. m-Chlorophenylpiperazine (mCPP) acts as an agonist to serotonin 2C, 1A, 1B, and 1D receptor subtypes and is applied in challenge tests. The object of this study was to develop a pharmacokinetic-pharmacodynamic model to describe the effects of mCPP on pituitary hormone secretion. METHODS: The hormone and mCPP plasma concentrations were determined after intravenous and oral administration of mCPP to 12 healthy men. The kinetic parameters of mCPP were compared to the drug's effect on hormonal response. RESULTS: After mCPP treatment, ACTH, cortisol, and prolactin levels were significantly increased compared to placebo. There was also a significant increase in clinical response (anxiety, shivering, dizziness, heightened sensitivity toward light and noise, and fear of losing control). Maximum mCPP concentrations varied 2.3-fold after intravenous infusion and 8-fold after oral administration. The absolute bioavailability ranged from 12% to 84%. mCPP's elimination half-life ranged from 2.4 h to 6.8 h after intravenous infusion and from 2.6 h to 6.1 h after oral application. However, the kinetic data as well as the pharmacodynamic response varied to an extent that precluded pharmacokinetic-pharmacodynamic modeling. The wide interindividual variability in mCPP's disposition kinetics could not be fully explained by genetic variation of the mCPP-metabolizing enzyme cytochrome P4502D6, which was determined in all probands. DISCUSSION: Other factors contributing to the variability in disposition kinetics could not be ruled out in this study, suggesting that mCPP is not a suitable model drug to test serotonin 2C receptor activity in vivo.

Initial serotonin transport into viable platelets and imipramine binding to platelet membranes.

Transport of serotonin into human platelets is a paradigm for neuronal reuptake to investigate putatively low neurotransmitter availability in certain psychiatric diseases. However, inconsistent results have been obtained on serotonin binding to platelet membranes at equilibrium and transport during initial phase into isolated platelets. In the present study we applied a rapid oil-centrifugation technique to study (14)C-serotonin transport for 15s into viable human platelets during the initial phase, compared to the binding of (3)H-imipramine at equilibrium (60 min) to membranes isolated from platelets of the same individuals and to their blood serotonin levels. Platelets were viable for two h after the isolation procedure; concomitant with the decrease in viability transport also decreased. Initial transport into viable cells was observed for two min. Across 19 healthy individuals blood serotonin levels correlated with the halfmaximal saturation constants of binding, K(D), for imipramine but not with any other transport or binding parameters, such as V(max) or B(max). Inhibition studies with psychoactive drugs showed good correlation between transport during the initial phase and binding at equilibrium (r = 0.83). It is speculated that changes in the V(max) of transport reflect problems with isolation, pretreatment with drugs, the energy load of the cell, and polymorphism of the serotonin transporter. The latter shows a polymorphism in the 5'regulatory region with a 44-bp insertion (l, long form) or deletion (s, short form). Results by Greenberg et al. indicate that in platelets from healthy men the l-variant was associated with increased initial serotonin uptake. Thus for genotyping, we suggest to subdivide patient and control groups in addition to psychopathology also according to their peripheral biochemical lesions.

Allelic variants of the serotonin(2C) receptor and neuroendocrinological responses to the serotonin(2C) receptor agonist m-chlorophenylpiperazine in healthy male volunteers.

The neurotransmitter serotonin (5-HT) possesses several receptors and their subtypes, some of which are polymorphic, such as the 5-HT(2C) receptor. The latter has been implicated in the control of neuroendocrine function, and has been discussed in the pathophysiology and pharmacotherapy of psychiatric disorders such as obsessive-compulsive disorder, panic disorder and bipolar affective disorder. To investigate whether the 5-HT(2C) receptor polymorphism contributes to the variation of neuroendocrinological responses elicited by activation of the hypothalamic-pituitary axis, we performed an m-chlorophenylpiperazine (m-CPP) challenge and monitored m-CPP and ACTH, cortisol and prolactin plasma levels in 16 healthy male volunteers carrying the common 5-HT(2C)-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT(2C)-ser-23 receptor gene. The 5-HT(2C) polymorphism contributed little to the variation of the scores regarding hormonal responses of ACTH, cortisol and prolactin to the m-CPP challenge. The group carrying the rare 5-HT(2C)-ser-23 receptor gene showed a faster and stronger but not statistically significant ACTH response to the challenge. However, it is noteworthy that there is a 'medium' effect size of the ACTH response according to the conventions of Cohen, and thus comparable to other studies. Both groups show similar major scores in the Temperament and Character Inventory (TCI).

Confirmation of the association between bleomycin hydrolase genotype and Alzheimer's disease.

Bleomycin hydrolase (BH), a cysteine protease from the papain superfamily, is considered to be a candidate for the beta-secretase, which is presumably involved in the production of beta-amyloid peptide. The G/G genotype of BH was identified as a significant risk factor for the development of Alzheimer's disease (AD) in subjects not carrying the apolipoprotein E epsilon4 allele (apoE-epsilon4). However, this finding was recently challenged. We studied this polymorphism in a homogenous sample of German AD patients and controls. The over-representation of the G/G genotype in AD patients could be confirmed, however it was more pronounced in apoE-epsilon4 carriers. Additional studies should be undertaken to increase the confidence that the BH polymorphism is associated with AD and to explore the relationship between BH and apoE.

The risk of acute suicidality in psychiatric inpatients increases with low plasma cholesterol.

Several studies suggest that the reduction of total cholesterol in blood by lipid-lowering agents is accompanied by a decrease in the incidence of coronary heart disease, but not in total mortality. Likewise, epidemiological studies show that low total cholesterol concentrations appear to be associated with an increased risk of death from suicide and injuries. There is little information with respect to acute suicidality and cholesterol in psychiatric inpatients; therefore the aim of the present study was to examine exactly this relation between plasma cholesterol and acute suicidality. The study comprised 45 acutely suicidal psychiatric inpatients, 95 nonsuicidal inpatients with affective disorder, and 20 healthy subjects. Psychopathological measures (Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, Beck's Suicide Intent Scale) were established in these patients as well as the plasma concentrations of cholesterol in patients and healthy subjects. The most important finding of this study is that the risk of acute suicidality decreases with increasing total cholesterol levels irrespective of age, gender, and nutritional status (i.e., body mass index). Comparison of total cholesterol levels between age- and sex-matched suicidal and nonsuicidal patients with affective disorder supports this observation: Despite the slightly higher body mass index, suicidal patients have significantly lower cholesterol levels than nonsuicidal patients. Our findings support the notion that acute suicidality is associated with low plasma cholesterol; this observation needs to be further studied in the context of a biological marker for suicide risk.

Upregulation of the platelet Serotonin2A receptor and low blood serotonin in suicidal psychiatric patients.

Suicidality has been found to be associated with low pre- and postsynaptic serotonin functioning. The purpose of this study was to examine whether in acutely suicidal psychiatric inpatients, the blood serotonin concentration was related to the underlying psychiatric disorder and whether it was associated with changes in the affinity (dissociation constant, KD) or in the maximal binding capacity (Bmax) of the platelet serotonin2A receptor. We therefore determined the blood serotonin concentrations and the platelet serotonin2A receptor activities of 45 suicidal psychiatric patients and 20 healthy subjects. We found that the blood serotonin concentrations were significantly lower in suicidal patients compared to healthy subjects. In all diagnostic categories (affective disorder, schizophrenia and adjustment disorder) we noted a significantly higher maximal binding capacity of the platelet serotonin2A receptor. These findings support the notion that a reduction in the availability of serotonin and an upregulation of the serotonin2A receptors in psychiatric patients are associated with a loss of control over suicidal impulses.

[Incidence of goiter in the Naumburg district]. / Untersuchungen zur Strumahäufigkeit im Kreise Naumburg.

10% of the inhabitants of the district of Naumburg were examined for their state of the thyroid gland. The average morbidity of struma was 25.2%. Above all the struma stages I and II were found. The maxima of frequency were in the age groups of the 20--29-year-old persons with 68% in the females and 27.4% in the males. Of the 585 inhabitants of the village Grossjena (85% of the total population) 32.9% has a struma. The patterns of distribution corresponded, apart from a second peak in the females at the time of the climacterium, to the patterns found in the whole region of Naumburg. The average iodine excretion in the urine of 19.9 micrograms/g creatinine was still undercut by the 12- to 15-year-old pupils of this village with 14.8 micrograms/g creatinine. The relation of female to male carriers of struma was on an average at 2.5 : 1. In individual age groups the sex-conditioned differences were eliminated. Relation of sex, excretion of iodine and frequency of struma confirm the endemic character of the struma disease in the district of Naumburg and confirm an iodine deficiency of IInd to IIIrd degree. The results intensely emphasize the necessity of a centrally regulated iodate prophylaxis.