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 association between catechol-O-methyl-transferase Val108/158Met polymorphism and suicide.

One of the candidate genes for suicide is also a gene in the pathway for catecholamine degradation encoding an enzyme catechol-O-methyl-transferase (COMT). It harbors a common functional polymorphism, a G to A nucleotide transition resulting in amino acid substitution from valine (Val) to methionine (Met) at position 158 (COMT Val(108/158) Met; rs4680), that has been associated with psychiatric disorders characterized with an increased risk of suicidal behavior. We have performed the first study on Caucasian population examining the association between completed suicide and the COMT Val(108/158) Met polymorphism. The study population consisted of 356 suicide victims and 198 control subjects. Significant difference in COMT Val(108/158) Met variants' (genotypes, alleles and Val carriers) distribution was found only in male groups, between controls and suicide victims (P = 0.018, P = 0.031, P = 0.005), and between controls and violent suicide victims (P = 0.026, P = 0.042, P = 0.010). The r value from the standardized residuals showed that the Met/Met genotype (r = 2.03) in the control group contributed to these significant differences. In contrast to male subjects, no significant differences in the frequency of the COMT Val(108/158) Met variants were detected between female control and female suicide groups; however, the power of calculation (range 0.161-0.680) was below the desired 0.800. In addition, the logistic regression analysis confirmed these significant differences. In conclusion, our results showed the overpresentation of the Met/Met genotype in male control subjects compared with male suicide victims, suggesting that this genotype of the COMT Val(108/158) Met might be a protective factor against suicide.

The effects of olanzapine and fluphenazine on plasma cortisol, prolactin and muscle rigidity in schizophrenic patients: a double blind study.

Pharmacotherapy of schizophrenia is associated with the stressful side effects. Muscle rigidity causes distress, discomfort and poor compliance. The aim of the study was to determine the relationship between plasma hormones (cortisol and prolactin/PRL) and muscle rigidity in female schizophrenic patients treated with olanzapine or fluphenazine. In a randomized, double-blind 22-weeks study, 12 patients were treated with olanzapine (5-20 mg/day) and 10 patients received fluphenazine (6-21 mg/day). Treatment with olanzapine moderately decreased, while treatment with fluphenazine significantly increased plasma cortisol levels and muscle rigidity. The marked and moderate increase in plasma PRL levels were found in patients treated with fluphenazine and olanzapine, respectively. The results suggested that olanzapine induced moderate neuroendocrine effects and a reduction in rigidity as compared to fluphenazine treatment.

Platelet serotonin concentration in dialysis patients with somatic symptoms of depression.

Platelet serotonin (5-HT) concentration was measured in 65 male and 45 female chronic renal patients on hemodialysis (HD) with different somatic symptoms of depression (crying spells, irritability, sleep disturbance, fatigability, loss of appetite, weight loss, somatic preoccupation and loss of libido), to find out the relationship between the severity of symptoms and platelet 5-HT concentration. Male and female patients had significantly lower platelet 5-HT concentration than 62 male and 38 female healthy subjects. Gender-differences in platelet 5-HT values observed in healthy subjects were not found in patients. Platelet 5-HT concentration differed in the groups of patients with the different scores of particular somatic symptoms (loss of appetite and loss of libido), but was similar in patients with other somatic symptoms. There was no relationship between platelet 5-HT concentration and the severity of somatic symptoms, or between platelet 5-HT concentration and age of the patients. Gender-related differences in the occurrence of somatic symptoms were detected in patients with the different degrees of weight loss, somatic preoccupation and loss of libido. Our results suggest that platelet 5-HT concentration could not be used as a biological marker for the severity of somatic symptoms in chronic renal patients on HD.

TCH-346 (Novartis).

TCH-346, an anti-apoptotic compound, is under development by Novartis for the potential treatment of Parkinson's disease (PD) and motor neuron disease [271447,342937]. By September 1999, phase I clinical trials for PD were underway [342937]. The compound was discovered in a screen for molecules with both norepinephrine uptake and MAO inhibiting properties but, although it had anti-apoptotic properties, it did not inhibit MAOA or MAO-B [333136,332004]. The compound increases lifespan in the progressive motorneuropathy mouse model and prevents ischemia in models of ischemia and seizure [288893]. In vivo, it shows neurorescuing and anti-apoptotic properties in PC12 cells and cerebellar granule cells, among others, at concentrations of 0.1 pM to 10 microM, suggesting that its action might prove potentially useful against Alzheimer's and/or Parkinson's disease [332004]. The compound has also shown neurorescuing properties in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia and mouse nigral dopaminergic (DA) neurons after treatment with MPTP in doses ranging between 0.0003 and 0.1 mg/kg po or sc, depending on the model [333136]. Data presented by the University of Nijmengen and the Free University of Amsterdam show that TCH-346 improves the behavioral and enzymatic outcome in the rat 6-OH-dopamine model of Parkinson's disease. TCH-346 (0.0014 mg/kg sc bid) prevented abnormal stepping (open field test) and prevented increases in fore and hind-paw retraction time. TCH-346 also improved acquisition in the Morris water maze task and, at doses between 0.0014 and 0.14 mg/kg, prevented reduction in tyrosine hydroxylase immunoreactivity [345259]. Affinity binding studies with TCH-346 showed that GAPDH is the target [294902,283200]. Differential display RT-PCR also showed that protein-isoaspartyl-methyl transferase is induced by the drug [283200].

Sex differences, season of birth and platelet 5-HT levels in schizophrenic patients.

Similar occurrence of schizophrenia was observed in men and women independent of their season of birth. Platelet 5-HT concentration was determined in 116 healthy control subjects (61 male and 55 female) and 152 patients with schizophrenia (96 male and 56 female). Platelet 5-HT concentration was significantly higher in male than in female healthy persons and schizophrenic patients. Male and female healthy subjects born in different seasons had similar platelet 5-HT concentrations, whereas schizophrenic patients with different birth-seasons had significantly different platelet 5-HT concentrations. The highest platelet 5-HT levels were observed in both male and female schizophrenic patients born in winter when compared to matched healthy controls. Male schizophrenic patients born in winter had higher platelet 5-HT levels than schizophrenic men born in spring and summer. Female schizophrenic patients born in winter had higher platelet 5-HT than schizophrenic women born in all other seasons. These results indicated sex differences in platelet 5-HT levels in healthy persons and schizophrenic patients. The relationship between season of the birth and platelet 5-HT concentration observed only in schizophrenic patients added further support to the presumption that schizophrenia is connected with a disturbance in the central serotoninergic system.

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.

EPHAR 99--Second European Congress of Pharmacology. 3-7 July 1999, Budapest, Hungary.

This meeting was chaired by Dr ES Vizi (Chairman of the Hungarian Pharmacological Society) and was attended by approximately 1600 delegates from 62 countries, including the USA, Canada, Israel, Japan and various parts of Europe. The opening ceremony was honored by the plenary lecture of a Nobel prize winner, Dr J Axelrod. The conference consisted of plenary sessions, 57 symposia and poster sessions. Each day the program included seven morning and seven afternoon symposia, simultaneously held, and a large poster section. The symposia focused on the neurotransmitter receptors as targets for the action of new drugs, new trends in the treatment of diabetes, Alzheimer's and Parkinson's diseases, psychiatric disorders, cardiac and gastrointestinal diseases and neuronal damage. All abstracts (more than 1200) were published in Fundamental and Clinical Pharmacology (1999) 13(Suppl 1). This year's meeting was substantially larger than the first EPHAR congress held in Milan, Italy, in 1995. It was generally well organized and served to introduce new basic and clinical knowledge in pharmacology.

The effect of MDMA (3,4-methylenedioxymethamphetamine) on the 5-HT synthesis rate in the rat brain: an autoradiographic study.

The effect of MDMA (3,4-methylenedioxymethamphetamine), a psychotropic amphetamine derivative, treatment on the rate of serotonin (5-hydroxytryptamine; 5-HT) synthesis in the rat brain was studied by autoradiography using alpha-[14C]-methyl-l-tryptophan method. Three different treatment protocols were compared to the control (saline) treated rats: (1) rats treated twice with 10 mg/kg every 12 h (20 mg/kg total) and injected tracer for the synthesis measurements 15 h later; (2) rats treated with four injections of 5 mg/kg every 12 h (20 mg/kg total) and injected tracer for the synthesis measurement 17 h after the last dose; and (3) rats given eight injections of 5 mg/kg every 12 h for four days (40 mg/kg) and used in the synthesis study 14 days after the last dose. Results showed a significant decrease in the rate of synthesis in the majority of cerebral structures examined in the 10 mg/kg group. In contrast the group receiving the same total amount (20 mg/kg) of MDMA but over two days (4x5 mg/kg) showed a significant increase in 5-HT synthesis in comparison to controls. The 5-HT synthesis rates measured 14 days after the last dose (four days, 8x5 mg/kg) were significantly reduced. The findings suggest that MDMA can produce either an increase or a decrease in the 5-HT synthesis a short time after a total dose of 20 mg/kg depending on the dose fractionation. However, 14 days after total dose of 40 mg/kg given over four days the synthesis rate was significantly reduced in many brain structures. The latter suggests a possible effect of the MDMA neurotoxicity on the serotonergic neurons, in addition to a possible influence on 5-HT synthesis via a feedback mechanism.

Platelet 5-HT and plasma cortisol concentrations after dexamethasone suppression test in patients with different time course of schizophrenia.

Platelet 5-HT and plasma cortisol concentrations were determined in 59 schizophrenic patients with different time course of illness before and after dexamethasone suppression test (DST). An abnormal DST (nonsuppression) was observed in 51% of patients. In these patients basal cortisol and platelet 5-HT concentrations were higher than in patients with normal DST. After DST, plasma cortisol levels were higher in nonsuppressors with intermittent and intermittent-chronic time course, whereas platelet 5-HT concentrations were increased in nonsuppressors with intermittent-chronic time course. The results suggest that schizophrenic patients have dysregulated hypothalamic-pituitary-adrenal axis as shown by a high rate of DST nonsuppression, and that nonsuppressors showed hypercortisolemia and hyperserotonemia independent of the time course of schizophrenia. No significant association between DST and time course of the illness was found.

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.

Serotonin synthesis increased in terminals four days after reserpine treatment: an autoradiographic study in rat brain.

The rate of 5-HT synthesis was determined in discrete rat brain regions 4 days after a single dose of reserpine (10 mg/kg) or reserpine carrier (controls), using an autoradiographic method with labelled alpha-methyl-L-tryptophan as a tracer. The results show that the rate of 5-HT synthesis was unchanged in the dorsal and median raphe, significantly decreased in the raphe magnus, and significantly increased in areas rich in serotonergic nerve terminals (i.e., hypothalamus, hippocampus, median geniculate body, parietal and visual cortices). An increase in tryptophan hydroxylase activity could account for the increase in the rate of serotonin synthesis seen in some regions. Since the 5-HT synthesis rate showed regional variability there seems to be a need for regional studies of the effect of drugs on the 5-HT synthesis. In addition, the 5-HT synthesis rate was not significantly different from that in controls in many of the brain regions.

Platelet 5-HT levels and hypothalamic-pituitary-adrenal axis activity in schizophrenic patients with positive and negative symptoms.

Hypothalamic-pituitary-adrenal (HPA) axis activity and platelet 5-HT concentrations were determined before dexamethasone suppression test (DST) in 80 male schizophrenic patients with predominantly positive or negative symptoms. Significant differences in platelet 5-HT and no differences in baseline plasma cortisol concentrations among schizophrenic suppressors and nonsuppressors were found. A similar rate of nonsuppression (56% positive and 53% negative schizophrenic patients) was detected. Platelet 5-HT, but not plasma cortisol concentrations, could be used to differentiate positive and negative symptoms of schizophrenia.

Hypothalamic-pituitary-adrenal axis function and platelet serotonin concentrations in depressed patients.

Plasma cortisol and platelet serotonin (5-hydroxytryptamine, 5-HT) concentrations were determined in 39 male psychotic and 39 male non-psychotic depressed inpatients, and in 69 male healthy control subjects. Psychotic or non-psychotic depressed patients had higher predexamethasone plasma cortisol levels than found in the control group. After the dexamethasone suppression test (DST), psychotic and non-psychotic depressed patients were subdivided into suppressors and non-suppressors. Psychotic and non-psychotic patients had significantly different platelet 5-HT concentrations among themselves and compared with the control group. However, there was no significant correlation between plasma cortisol levels and platelet 5-HT concentrations. Dexamethasone administration did not affect platelet 5-HT concentrations within subtypes of depressed patients. Abnormal cortisol suppression after the DST occurred more frequently in psychotic than in non-psychotic patients. Platelet 5-HT and plasma cortisol concentrations were decreased in patients with pronounced suicidal behaviour. Our results suggest that plasma cortisol and platelet 5-HT concentrations might serve as independent biological markers for different subtypes of depression.

Influence of fluoxetine on regional serotonin synthesis in the rat brain.

The aim of the present study was to test the hypothesis that there should be a difference between the effects of an acute and an 8-day (chronic) administration of fluoxetine (10 mg/kg) on the rate of serotonin [5-hydroxytryptamine (5-HT)] synthesis. The 5-HT synthesis rate was measured in discrete regions of the rat brain using the alpha-[14C]methyl-L-tryptophan autoradiographic method. The results show that the acute and chronic fluoxetine treatments influence the 5-HT synthesis rate in different ways. A single dose of fluoxetine induced a significant increase in 5-HT synthesis in the visual, auditory, and parietal cortices, substantia nigra, hypothalamus, ventral thalamus, and dorsal hippocampus. In contrast, after a chronic treatment a decrease was observed in the substantia nigra, caudate, and nucleus accumbens, the auditory, parietal, sensorimotor, and frontal cortices, and ventral tegmental area. A significant decrease in the rate of 5-HT synthesis was observed in the dorsal raphe after both the single and chronic treatments. The results suggest that extracellular 5-HT has a delayed influence on the brain 5-HT synthesis rate in structures with serotonergic terminals. The findings from the acute study could be important for patients who have just started receiving fluoxetine treatment, as an increase in the 5-HT synthesis rate might occur in the acute phase of their treatment. In addition, the findings, from the chronic treatment study might give us a better understanding of how the brain serotonergic system adapts during a prolonged exposure to extracellular 5-HT.

DL-fenfluramine increases the 5-HT synthesis rate in the terminals while decreasing it in the cell bodies of the rat brain.

The rate of 5-HT synthesis in discreet rat brain regions was determined using the alpha-[14C]methyl-L-tryptophan autoradiographic method. DL-Fenfluramine (10 mg/kg, i.p.), given 20 min before tracer injection, decreased the rate of 5-HT synthesis in the serotonergic cell bodies (-32% in dorsal and -23% in median raphe nuclei) but increased the rate in almost all the terminal areas investigated when compared to the rate in the control (saline treated) rats. The most pronounced increase was observed in the cortex (% difference of control between +22% and +49% in auditory and parietal-sensory-motor cortex, respectively), striatum (+32% in globus pallidus; +17% median part of caudatus-putamen), superior olive (+36%), dorsal hippocampus (+33%) and ventral thalamus (+29%). Our results suggest that axon terminals respond by increasing 5-HT synthesis, after enhanced release of 5-HT from terminals induced by fenfluramine. This increase in 5-HT synthesis in the terminals probably occurs as part of the compensatory mechanisms that replenish the loss of neurotransmitter from the terminal releasible pool. At the same time our data suggests that the fenfluramine-induced release of 5-HT in the cell bodies inhibits synthesis of the 5-HT through an autoreceptor.

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.

Effect of age on platelet 5-HT concentrations in healthy controls, depressed and schizophrenic patients.

The influence of age on platelet 5-HT concentrations was investigated in 85 male unipolar depressed inpatients, 113 male schizophrenic inpatients and 81 normal male controls. The correlation coefficients between platelet 5-HT concentrations and age within groups were very low and nonsignificant. Our results suggest that higher platelet 5-HT content, observed in schizophrenic patients, could not be ascribed to the influence of age.

The acute effects of reserpine and NSD-1015 on the brain serotonin synthesis rate measured by an autoradiographic method.

The rate of serotonin (5-HT) synthesis was measured in the discrete regions of the rat brain utilizing an autoradiographic method and alpha[14C]methyl-L-tryptophan as a tracer after an acute treatment with reserpine (10 mg/kg IP) or NSD-1015 (m-hydroxybenzylhydrazine) (100 mg/kg IP). Controls were injected with the same volume of solvent in place of reserpine or NSD-1015. Our results showed that reserpine induced a statistically significant (except for medial geniculate body) decrease in the rate of 5-HT synthesis in a large number of discrete brain structures. Reserpine had no influence on the plasma concentration of amino acids sharing the same carrier with tryptophan nor on the fraction of plasma-free tryptophan. NSD-1015 induced a statistically significant increase (p < .05) in the rate of 5-HT synthesis in 20 out of 28 brain regions but produced a pronounced decrease in the rate of 5-HT synthesis in the pineal body. This decrease in the pineal body serotonin synthesis rate is most likely the result of the loss of the label in the form of 5-hydroxy-alpha[14C]methyl-L-tryptophan [5-OHMTrp] that is not metabolized further because aromatic amino acid decarboxylase was inhibited. The data showing that there was no loss of the 5-OHMTrp from other brain structures as result of reserpine are also given. NSD-1015 treatment also induced a time-dependent increase in the plasma concentration of free tryptophan that becomes significant 30 minutes after NSD-1015 injection. Our results suggest that reserpine induces a decrease in 5-HT synthesis probably via direct or indirect inhibition of tryptophan hydroxylase activity. Since NSD-1015 alone increased the rate of 5-HT synthesis, the measurement of 5-HT synthesis in previous experiments using NSD-1015 and measuring the rate of 5-hydroxytryptophan accumulation after NSD-1015 induced inhibition of decarboxylase activity should be interpreted with reservation.

Autoradiographic evaluation of the influence of hypothalamic 5,7-dihydroxytryptamine lesion on brain serotonin synthesis.

The influence of a unilateral stereotaxically induced 5,7-dihydroxytryptamine (5,7-DHT) lesion in the dorsolateral hypothalamus on brain serotonin synthesis was evaluated by an autoradiographic method, using labelled alpha-methyl-L-tryptophan (alpha-MTrp). The hypothalamus was selected as the lesion site because it receives well defined and relatively large projections from the raphe nuclei. Data suggest that the unilateral lesion in the dorsolateral hypothalamus had a significant influence (an increase) on the rate of serotonin synthesis in the large majority of ipsilateral brain structures examined. It seems that the effect was the greatest in the hippocampal structures, the thalamus, and the parietal and sensory motor cortices. The average increase in the rate of serotonin synthesis on the lesion side when compared with the contralateral side was between 3% (amygdala) and 52% (dorsal hippocampus; CA3 layer of hippocampus). Since in the sham-injected rats (same volume of saline) there was no obvious injection-contralateral side asymmetry observed (except for two structures, probably affected by the injection needle, which showed a significant difference), we concluded that the effect observed in the present study was most likely related to the 5,7-DHT-induced lesion on the serotonergic terminals in the hypothalamus. Comparison of the rate of synthesis in the dorsal and medial raphe and the pineal body with the rates reported earlier for these structures led us to conclude that either the 5,7-DHT lesion in the hypothalamus did not influence the rates in these structures in their entirety, or the method used was not sensitive enough to reveal this influence. Data reported here also demonstrate how a highly specific tracer (alpha-MTrp), in conjunction with a specific and localized lesion, could aid our understanding of the brain serotonergic system.