Nitric oxide and neopterin in bipolar affective disorder.

BACKGROUND: There is an increasing interest in the role of nitric oxide (NO) and pterines in the pathophysiology of neuropsychiatric disorders. The results so far show an inconsistent pattern. METHODS: In the present study, neopterin and a measure of NO synthesis in plasma of symptomatic and euthymic bipolar affective patients were compared to those of patients with a major depression and healthy controls. As an index of NO synthesis, the ratio of the amino acids citrulline and arginine (Cit-Arg ratio) was calculated. Neopterin is a bypass product in the synthesis of tetrahydrobiopterin, which is a cofactor of NO synthase. RESULTS: The results indicate that both neopterin and the Cit-Arg ratio are decreased in bipolar affective patients, irrespective of their symptomatic status. In addition, an association between the values of the Cit-Arg ratio and the neopterin level was observed, which is suggestive for a low tetrahydrobiopterin activity. CONCLUSION: NO formation may be endangered in bipolar affective disorder.

Bipolar mania and plasma amino acids: increased levels of glycine.

Previous studies have suggested that the N-methyl-d-aspartate (NMDA) glutamate receptor complex is implicated in the pathophysiology of several neuropsychiatric disorders. Especially the glycine coagonist site of this receptor has been proposed as a therapeutic target. It has been hypothesized that the NMDA receptor and the serotonergic system, which function is compromised in affective disorders, are functionally coupled. Furthermore, several studies suggest that peripheral levels of amino acids are associated with psychotic symptomatology. We therefore measured plasma levels of glutamate, glycine, tryptophan and the tryptophan ratio in 20 bipolar-I patients during the manic phase and at remission of symptomatology. Data were compared to a matched group of healthy controls and a group of euthymic bipolar-I patients. During the manic phase, a significant increase of both glutamate and glycine was found, that persisted at remission. Tryptophan and the tryptophan ratio were decreased in manic patients. Subsequent analysis showed that changes in glutamate, tryptophan and tryptophan ratio could be attributed to the use of anticonvulsants. The increased glycine, however, was not related to the use of mood stabilizers. Although the exact relationship between peripheral measures of amino acids, e.g., glycine is not fully clear, the results of this study suggest an involvement of glycine and/or its coagonist site of the NMDA receptor in a manic relapse of patients with a bipolar-I disorder.

Plasma amino acids and sports injuries.

The aim of this study was to explore the relationship between changes in plasma amino acids and the incidence of sports injuries during a soccer season. Fourteen plasma amino acids were assayed at monthly intervals in 12 young soccer players during a whole soccer season. Based on the number and severity of injuries the soccer players were divided into an injury-prone and a non-injury-prone group. The mean plasma level of the amino acid glycine was significantly lower ( P=0.009) in the injury-prone group than the other group, while the mean plasma levels of tyrosine, tryptophan and lysine were higher in the injury-prone group during this period ( P<0.05). However there were no significant differences in the calculated plasma tryptophan and tyrosine/large neutral amino acids ratios. Significant linear time trends were observed for taurine, ornithine, lysine and the tryptophan/large neutral amino acids ratio.These results indicate that the plasma concentrations of glycine and to a lesser extent those of tyrosine, tryptophan and lysine may be promising peripheral markers for injury-proneness in young soccer players. Whether a role for glycine substitution will be indicative to reduce the occurrence of sports injuries will need to be investigated in future studies.

Effects of imipramine, fluvoxamine and depressive mood on autonomic cardiac functioning in major depressive disorder.

OBJECTIVE: Diminished HR variability is considered to be associated with depression and the increased risk of cardiovascular disease. The pharmacological effects of antidepressants and depressive mood itself may contribute to alterations in autonomic cardiac functioning, but a limited amount of data is available. We studied the effects of two different types of antidepressant treatments (imipramine and fluvoxamine), in addition to the effect of depressive mood, on the cardiovascular system in depressed patients. METHODS: Depressed inpatients were studied during a drug-free period and after 4 weeks of adequate treatment with imipramine (n = 17) or fluvoxamine (n = 24). Heart rate variability, blood pressure variability, and a baroreflex sensitivity index during supine rest and orthostatic challenge were analyzed by means of spectral techniques to obtain noninvasive parameters of sympathetic and parasympathetic activity. RESULTS: Both imipramine and fluvoxamine reduced sympathetic and parasympathetic activity, although the effects of imipramine were much more pronounced. Severity of depression was positively related to mean levels of heart rate and blood pressure in the total patient group. There was no convincing evidence that these relationships differed between depressed patients treated with imipramine and those treated with fluvoxamine. CONCLUSION: Our findings suggest that alterations in mean heart rate and blood pressure in depressed patients after antidepressant treatment are the result of a combined effect of pharmacological actions of antidepressants and improvement of depressive mood state. The present study did not confirm the relationship between clinical state and cardiovascular variability or baroreflex sensitivity.

The acute transient polymorphic psychosis: a biochemical subtype of the cycloid psychosis.

BACKGROUND: The pathogenesis of atypical psychoses, in particularly those characterized by polymorphic psychopathology, is hypothesized to be related to disturbances in amino acid metabolism. OBJECTIVE: In the present study, the role of the amino acid serine was investigated in patients with acute transient polymorphic psychosis. METHODS: Patients were loaded with serine and with the amino acids glycine and alanine as controls and subsequently evaluated for the development of psychopathological symptoms. In addition, plasma levels of amino acids were measured. RESULTS: In a subgroup of patients suffering from atypical psychoses, this biochemical challenge resulted in the reappearance of psychedelic symptoms in particular. Furthermore, significantly lower plasma concentrations of serine were found. In vitro experiments revealed a disturbance in the one-carbon metabolism. In another group of patients the loading provoked vegetative symptoms and fatigue. CONCLUSIONS: Disturbances in amino acid metabolism may be involved in the emergence of certain psychotic disorders.

Más allá de la corriente dominante: El valor heurístico de la Psicosis Cicloide

Los intentos para diagnosticar los trastornos psiquiátricos son tan antiguos como la propia Medicina y han ido siempre paralelos con su desarrollo científico. Los conceptos diagnósticos de la Psiquiatría actual están profundamente enraizados en la tradición europea del siglo XIX en la que existe una línea de desarrollo alemana y francesa junto con otra neuropsiquiátrica. A pesar de los intentos rigurosos por elaborar diagnósticos médicos acertados, las dificultades fundamentales relacionadas con la selección de signos y síntomas relevantes y la posterior validación de las entidades sindrómicas, todavía persisten. Uno de los ejemplos más interesantes es la psicosis cicloide que trasciende a las fronteras estrictas de las actuales taxonomías e introduce signos y síntomas alternantes relacionados con experiencias subjetivas y con trastornos de motilidad distintos de la catatonia. Aunque la práctica actual de categorización descriptiva puede ser útil a efectos de comunicación, nosotros propugnamos la aplicación de un modelo multiniveles tanto horizontal como vertical en el proceso de diagnóstico psiquiátrico (AU)

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Catatonia: the rise and fall of an intriguing psychopathological dimension.

BACKGROUND: For at least 125 years the discussion about the clinical relevance of catatonic symptoms in psychiatry continues. It started from the original description by Kahlbaum and was revived by modern factor analytical studies, that identified the catatonic dimension in about 10% of newly admitted patients. OBJECTIVE: Over a period of 2 years, four patients with an acute episodic psychosis and prominent catatonic symptoms were examined. METHODS: A clinical description is given of the psychopathology and classification is performed according to the various diagnostic instruments. RESULTS: All patients showed a circular fluctuation of their psychoses, with motor symptoms ranging from the excited to the inhibited pole within one episode. Their clinical pictures also comprised mood swings and anxieties as well as hallucinatory and delusional experiences, whereas the course of disease was characterized by complete recovery without residual symptoms. CONCLUSIONS: The significance of catatonic symptoms is not recognized in the current taxonomies despite the fact that this has major pharmacological treatment implications.

Pharmacokinetics of the beta-carboline norharman in man.

In healthy subjects, pharmacokinetics were characterised using single oral and sublingual administrations of the beta-carboline norharman. For this purpose, norharman levels in blood plasma were measured up to 90-105 min after both routes of administration. Dose proportionality of three different single oral doses of norharman (7, 65 and 110 microg/kg) administered as 0.52 and 5 mg capsules was evaluated at 8 time points. Peak levels were attained at 30 min after the oral load of norharman. Mean relative availabilities determined by the area under the curve (AUC) procedure were 14.3 and 98.0 nmol.min/l after oral dosing of 7 and 65 microg/kg, respectively. AUC values in women were 3-4 times higher than in men. Sublingual dosing of 6.5 and 13 microg/kg norharman encapsulated in 5 mg of cyclodextrins resulted in a much higher mean AUC and a more rapid absorption. Mean AUC after sublingual administration of 6.5 microg/kg was 929.8 nmol.min/kg and plasma levels were maximal 10-15 min after norharman was given. Moreover, apparently no sex difference was found using this way of application. Norharman disappeared from the plasma with half-lifes of 25-35 min, irrespective of the route of administration. Even at the highest measured norharman levels of 53 nmol/l plasma, no behavioral effects were observed. In addition, the subjects did neither report any effects nor any side-effects during the experiment. This is the first study in which the kinetics of ingested norharman have been measured in humans.

Effect of electroconvulsive therapy on biopterin and large neutral amino acids in severe, medication-resistant depression.

Biopterin, neopterin and the large neutral amino acids (LNAA), i.e. phenylalanine, tyrosine, tryptophan, isoleucine, leucine and valine were measured in plasma of 20 severely depressed inpatients before and after a course of electroconvulsive therapy (ECT). These patients showed a significantly lower plasma biopterin concentration at baseline in comparison with healthy controls. After treatment an increase in biopterin was found, which was statistically significant in the depressed patients with psychotic features. The plasma phenylalanine-tyrosine ratio, which previously increased, normalised after ECT. Mean tryptophan concentration was lower in depressed patients than in normal controls. The patients who responded to ECT showed an increase in the tryptophan concentration and its ratio (tryptophan/LNAA) after treatment. Our results suggest that ECT increases biopterin, which probably results in synthesis of amino acids, especially tyrosine. Furthermore, ECT seems to increase cerebral tryptophan availability because of less tryptophan catabolism parallel with biopterin activation. More research is required to see if biopterin could be useful as a biological marker for the depressive state in this subgroup of patients, because this compound seems to play an important role in the etiology and treatment of depression.

The acute effects of norharman on cocaine self-administration and sensorimotor function in male Wistar rats.

The purpose of the present study was to determine the acute effects of the beta-carboline norharman on cocaine dependence. Male Wistar rats were allowed to self-administer cocaine for 3 h for seven sessions. A single injection of norharman (0.2-20 mg/kg, i.p.) was given 30 min before the onset of the seventh session. It was shown that norharman decreased the cocaine intake in a U-shaped manner with the dose of 10 mg/kg having the most potent effect. These results indicate that several receptor mechanisms mediate the effects of norharman. In addition, 15 min following the administration of norharman on session 7, motor and sensory skill tests were performed. Six naïve animals were tested with the dose, which has the most pronounced effect on cocaine self-administration intake, in order to examine whether the observed effects were due to norharman or due to the combination of norharman and cocaine. It was observed that norharman in both the naïve and cocaine-exposed animals significantly increased the response time in the somato-sensory orienting test. However, only in the naïve animals a significant effect of norharman on the grasp reflex was observed.

Tryptophan: a precursor for the endogenous synthesis of norharman in man.

We investigated whether in healthy subjects L-tryptophan may serve as a precursor for the endogenous synthesis of the beta-carboline norharman. For this purpose subjects, smokers as well as non-smokers, received 0 or 1.2 g of an oral dose of tryptophan. Smokers started the experiment 2 h after cessation of smoking. Plasma levels of tryptophan and norharman were measured 100 and 125 min after the start of the experiment. The levels of both compounds were significantly higher in the group receiving tryptophan. Norharman concentrations in the plasma of smokers were significantly higher than in the non-smoking subjects under both experimental conditions. These results add some proof to the hypothesis that in humans tryptophan may serve as a precursor for the synthesis of norharman.

Prescribing patterns in patients using new antidepressants.

AIMS: To study possible selective prescribing ('channelling') we compared characteristics of patients using the SSRI sertraline with patients using longer available SSRIs. METHODS: An observational cohort study in 1251 patients being prescribed an SSRI. RESULTS: In contrast to other studies, we found no evidence for channeling of sertraline. Sertraline was mainly prescribed for the labelled indication (depressive disorder), while older SSRIs were more often prescribed also for other indications. Time on the market was inversely associated to the proportion of patients treated for depressive disorder. CONCLUSIONS: We found no evidence for channeling of sertraline compared with prescribing patterns of older SSRIs.

Towards an objective quantitative assessment of daily functioning in migraine: a feasibility study.

Migraine is a chronic disabling disorder, with migraine episodes significantly reducing quality of life and leading to impaired functioning (physically, socially, emotionally) both at home and at work. We explored whether ambulatory accelerometry can be used as an objective method to quantify the behavioral aspects of migraine-related disability. Four body mounted uni-axial piezo-resistive accelerometers were used to quantify the time spent in different body postures (lying, sitting, standing), physical activities (walking, cycling) and a general index of body motility during eight migraine attacks and subsequent recovery periods of six patients in their habitual environment. The migraine attacks and recovery periods could be monitored after about 1 h, which was the time required for the investigator to travel to the patient and for the sensors to be attached. In order to quantify the influence of a migraine episode on daily activities, we also performed measurements during a headache-free baseline period of the same patients. Overall, the procedures functioned well, indicating that ambulatory accelerometry measurements before, during and after a migraine attack are feasible to perform. Furthermore, our quantitative data revealed that migraine always influenced behavior by reducing overall body motility and that, dependent upon the severity of the attack, the effectiveness of acute treatment and the time of day, the time spent in various body positions, dynamic activities, and the number of postural transitions were affected. This feasibility study showed that ambulatory accelerometry can provide the objective behavioral effect parameters for the evaluation of migraine and its treatment on daily functioning in the habitual environment of migraine patients.

Is delirium after cardiac surgery related to plasma amino acids and physical condition?

The authors studied interrelationships between plasma levels of amino acids, physical condition (as apparent from cortisol, albumin, and thyroid hormone concentrations), and postoperative delirium in 296 patients undergoing elective cardiac surgery. Both plasma tryptophan (Trp) and ratio of Trp to the other large neutral amino acids (oLNAA) were reduced in delirious patients compared with control patients. The lower availability of Trp for the brain in delirious patients may lead to decreased serotonergic function. Besides, the ratio of phenylalanine (Phe) to the oLNAA was increased in delirium, which may result in a higher synthesis of cerebral dopamine and norepinephrine. Delirious patients were also in poorer physical condition than nondelirious patients, having decreased albumin level and increased ratio of inactive reverse triiodothyronine (T3) to active T3. Decreased Trp and increased Phe availability may give rise to an imbalance in cerebral neurotransmitters and thus contribute to delirium.

Personality traits and psychological reactions to mental stress of female migraine patients.

The purpose of this study was (i) to compare a range of stress-related personality traits, including defense and coping mechanisms, of migraine patients (n = 23) with those of tension headache patients (n = 18) and dermatologically afflicted, but otherwise healthy, controls (n = 22), and (ii) to compare their state anxiety and other moods before, during, and after the presentation of a psychological stressor (mental arithmetic). For all three groups, mental arithmetic induced a significant increase in state anxiety and mood disturbance, followed by a subsequent decrease during recovery. Migraine patients were not found to have a higher disposition for anxiety, depression, or rigidity than tension headache patients or controls. Between the headache groups no differences in the use of defense and coping mechanisms were found. Compared to the control group, however, both migraine patients and tension headache patients were more inclined to use internally focused defense mechanisms and less inclined to seek social support when confronted with a problem. The psychological reaction of migraine patients to mental stress hardly differed from tension headache and control subjects. Compared to the control subjects, however, both groups of headache patients exhibited a diminished recovery from feelings of vigour, depression, and fatigue due to the stress induced. It is suggested that this distinct psychological reaction to stress of headache patients versus healthy control subjects is related to the more internally focused defense style of the headache sufferers. Thus, in contrast to previous results, this study does not present evidence of a migraine personality. It suggests the development of specific personality characteristics as a consequence of suffering from episodic headache.

Incidence of and preoperative predictors for delirium after cardiac surgery.

Incidence of and preoperative predictors for postoperative delirium were studied in 296 patients (age 26-83 years, mean age 63 years) undergoing elective cardiac surgery. Delirium occurred in 40 (13.5%) patients. Predictors included old age, low level of albumin, poor physical condition, use of nifedipine, and a high ratio of the amino acids phenylalanine to the sum of isoleucine, leucine, valine, tyrosine, and tryptophan. These findings suggest that preoperative physical condition and amino acid disturbances may be related to delirium after cardiac surgery in the elderly.

Stress and self-injurious behavior; hormonal and serotonergic parameters in mentally retarded subjects.

Self-injurious behavior (SIB) and stereotyped behavior (SB) are major challenges for professionals in the field of mental retardation. From animal experiments it has become obvious that these behavioral disturbances are not purposeless but may emerge secondary to restrictive environment and may serve de-arousing objectives. In mentally retarded subjects, several hypotheses have been formulated concerning the pathogenesis of SIB, particularly about the involvement of serotonin and beta-endorphin, which are supported by beneficial treatment effects of the opiate antagonist naltrexone and serotonin modulating compounds, respectively. The present study was designed to investigate basal levels of stress-hormonal and serotonergic parameters as well as plasma levels of amino-acids and the beta-carboline norharman in a group of 64 mentally retarded subjects with SB and/or SIB. Allocation to three different groups comprising 17 retarded controls, 26 subjects with mainly SIB and 21 subjects with mainly SB, was originally performed using the scores on the factors Irritability, Stereotypic Behaviour and Hyperactivity of the Aberrant Behavioral Checklist. Because of the overlapping nature of the behavioral parameters, subjects were subsequently divided into three maximally contrasting groups, viz. predominantly SIB, predominantly SB and retarded controls, each comprising 11 subjects. With respect to beta-endorphin, no differences were found either between both the original and maximally contrasting groups or in comparison to nonretarded controls. As compared to retarded controls, a tendency to lower values for total cortisol and cortisol binding globulin appeared to be present in the SIB group, whereas in the SB group a tendency toward higher levels of the major serotonin metabolite 5-HIAA was found. In the contrasting SB group, a trend toward decreased total cortisol level was observed as compared to the retarded control group. In addition, significantly lower values for norharman and tryptophan were demonstrated in the total group of mentally retarded subjects as compared to non-retarded controls. The results of the present study, yielding co-existent disturbances in stress-hormonal and monoaminergic mechanisms as well as in the metabolism of norharman, are in line with the hypothesis that mentally retarded subjects are at risk for the development of stress-related behavioral disorders such as SIB and SB.

Atypical psychoses.

The European psychiatric literature is rich in descriptions and studies of atypical psychotic disorders. Most of these are finally deemed to be varieties of the affective or schizophrenic disorders, which in turn are regarded to be typical. The acute polymorphic psychotic disorder according to the ICD-10, and the periodic catatonia of Gjessing, although hardly recognized and acknowledged, are good candidates to be considered as separate psychotic disease entities.

Abnormal amino acid metabolism in patients with early stage Alzheimer dementia.

Plasma levels of several amino acids were studied in 14 patients with early stage probable Alzheimer's disease (AD) and 17 age-matched controls. In the AD patients a possible relationship between amino acid levels and behavioural symptomatology was also investigated. We found significantly reduced levels of tryptophan and methionine in plasma samples from the AD patients compared to the control subjects. Moreover, plasma tyrosine/large neutral amino acids (LNAA) ratio and the ratio of plasma taurine and the product of the plasma levels of methionine and serine (TSM-ratio) were significantly increased in the AD patients in comparison with the controls. However, no difference was found in plasma tryptophan/LNAA ratio and in homocysteine levels between both groups. Concerning the behavioural symptomatology no significant correlation was found between the Reisberg Behave AD scale and plasma amino acid levels or ratios. The reported findings suggest that abnormal amino acid metabolism is present in the early stages of AD. We hypothesize that this abnormality could play a role in the pathogenesis of behavioural changes occurring in later stages of AD.

Serotonergic, catecholaminergic, and cardiovascular reactions to mental stress in female migraine patients. A controlled study.

This study aimed at the combined assessment of the serotonergic and sympathetic nervous system reactions of migraine patients before, during, and after the induction of mental stress in order to detect the possible role of these reactions in inducing a migraine attack. The responses to mental stress of the migraine patients were compared to a group of patients suffering from tension headache and a control group. Activation of the sympathoadrenomedullary system due to mental stress was successfully induced in the migraine patients (n = 23), in the tension headache patients (n = 18), and in the control group (n = 22). The results of this study present evidence of increased cardiovascular activity in migraine patients as compared to nonmigraineurs. However, no evidence was found of a specific serotonergic, sympathoadrenomedullary, or cerebrovascular response of migraine patients to mental stress as compared to nonmigraineurs.