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.

Changes in serine metabolism by a serum factor present in a group of episodic psychotic patients.

Addition of serum, obtained from patients suffering from an acute psychosis characterized by dysperceptions, to the culture media of fibroblasts altered the amino acid metabolism in these cells. After subculturing of fibroblasts in the presence of serum obtained from these patients, the concentrations of both serine and methionine were decreased in the medium as well as in the fibroblasts. Moreover, the concentration of taurine in the fibroblasts was increased. The specific activities of serine hydroxymethyltransferase and cystathionine beta-synthase were also measured in the fibroblasts. It was found that both enzyme activities were significantly higher after subculturing with patients' serum as compared with serum obtained from healthy controls. It is concluded that a factor, present in the serum of these acute psychotic patients, is responsible for the observed changes in serine, taurine, and methionine concentrations in the fibroblasts as well as for the increased enzyme activities mentioned.

Seasonal variations in binding of 3H-paroxetine to blood platelets in healthy volunteers: indications for a gender difference.

Binding of paroxetine to blood platelet membranes was studied longitudinally in 20 healthy volunteers (11 men and 9 women) in order to determine seasonal and gender variations. Blood samples were obtained in September, December, March, and June, and repeated in September. A significant seasonal variation in the maximal number of binding sites (Bmax) was found. Men were found to have significantly lower (Bmax) values than women. Although the pattern of seasonal variation was not identical in men and women, no significant differences were detected. The affinity constant (KD) of paroxetine binding showed a significant seasonal variation. Men were found to have a significantly higher KD (lower affinity) than women. The pattern of seasonal variation was identical in men and women. These data support the evidence indicating a substantial seasonal effect on the serotonergic system, and show that in paroxetine binding studies, groups of subjects should be matched for season and gender.

Relationship between age and incidence of parkinsonism in psychiatric patients treated with haloperidol.

In a retrospective follow-up study of 230 psychotic patients treated with haloperidol, the incidence of parkinsonian side effects was greater in patients under 40 than in patients 40 years of age or older.

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.

Effects of alprazolam and lorazepam on catecholaminergic and cardiovascular activity during supine rest, mental load and orthostatic challenge.

Effects of oral alprazolam (0.5 and 1 mg) and lorazepam (2 mg) on sympathetic adrenomedullary activity and sedation were studied during supine rest, mental load (Color Word Test, CWT) and active standing (OCT), in 12 male volunteers in a randomized double-blind placebo-controlled cross-over design. Compared to placebo, alprazolam significantly increased subjective sedation, reduced plasma adrenaline and noradrenaline concentrations and mean blood pressure (MBP) during supine rest, and attenuated plasma adrenaline responses during the CWT and the OCT; these effects during the CWT and OCT appeared to be dose-dependent. In comparison with lorazepam (2 mg), alprazolam (1 mg) showed reduced MBP levels during supine rest, whereas lorazepam showed a higher heart rate level during supine rest, a reduced plasma noradrenaline response to the OCT and a performance deterioration to the CWT. There were no differences between alprazolam (1 mg) and lorazepam regarding subjective sedation. Although the benzodiazepines were similar regarding their increase of sedation, alprazolam and lorazepam induced differential effects on sympathetic adrenomedullary activity during rest and stress, whereby suppression of adrenomedullary activity may be specific for alprazolam.

Effects of lorazepam on cardiac vagal tone during rest and mental stress: assessment by means of spectral analysis.

Dose-dependent effects of intravenously administered lorazepam on haemodynamic fluctuations were studied by means of spectral analysis, in order to elucidate sympathetic and parasympathetic components in cardiovascular control during situations of rest and mental stress after benzodiazepine administration. In a double-blind randomized cross-over study, nine male volunteers participated in two sessions: a placebo and lorazepam session. During these sessions, the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.06, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). During the placebo session the subjects received five placebo injections. For five of the nine subjects the lorazepam session was their first session. Heat rate (HR), blood pressure (BP) and respiration were recorded continuously. Power spectra were calculated per 2.5-min periods for HR, systolic (SBP) and diastolic BP (DBP). Spectral density was assessed for three frequency bands: low (LFB: 0.02-0.06 Hz), mid (MFB: 0.07-0.14 Hz) and high (HFB: 0.15-0.40 Hz). During the consecutive periods of rest, lorazepam induced a dose-dependent decrease in HR, and a dose-dependent increase in LFB, MFB and HFB power of HR, but lorazepam had no effect on BP. The effects were significant after 0.44 mg lorazepam for HR and HFB power, and after 0.94 mg lorazepam for the HR fluctuations in the LFB and MFB. Lorazepam did not influence the cardiovascular responses to the CWT.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired glycine-serine conversion and increased plasma taurine levels in episodic psychotic patients with psychedelic symptoms.

A disturbance of serine-glycine metabolism has been demonstrated in patients suffering from episodic acute psychosis, characterized by sensory perceptual distortions in whom oral loading with either serine or glycine induced psychedelic symptoms. Fasting plasma amino acid levels in oral serine-responsive patients were compared with those in glycine-responsive and manic-depressive patients. Only serine-responsive patients had a decreased plasma serine and increased plasma taurine concentration, while glycine responsive patients showed decreased alanine and manic-depressive patients an increased plasma glycine level. Amino acid analyses of plasma samples obtained after serine loading in patients and controls suggest that serine-responsive patients had an impaired conversion of glycine into serine. The results suggest that the higher plasma taurine level in serine-responsive patients is caused by an increased synthesis of taurine from homocysteine and serine. The limiting capacity of methyltetrahydrofolate-homocysteine methyltransferase coupled to increased formation of taurine may be responsible for the serine-evoked psychotic syndrome.

Eicosanoid and amino acid metabolism in transient acute psychoses with psychedelic symptoms.

It has been hypothesized that a disturbance of glutathione (GSH) metabolism might be a common factor in many psychiatric disorders. The aim of the present study was to test this hypothesis in transient acute psychotic patients with distorted perceptions. Since the metabolism of GSH is related to that of thromboxane B2 (TXB2), prostaglandin E (PGE) and some amino acids, we determined these substances in the plasma of 15 patients and 17 normal controls. Plasma concentrations of TXB2 were significantly higher and concentrations of serine and tryptophan were significantly lower in patients than in controls. Large variation was observed in plasma PGE levels in patients, although mean values did not differ significantly from controls. These results are consistent with the hypothesis that the metabolism of GSH is impaired in transient psychotic states.

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.

Effects of clomipramine on plasma amino acids and serotonergic parameters in panic disorder and depression.

We examined the effects of long-term (six months) treatment with the serotonin potentiating tricyclic antidepressant clomipramine on several serotonergic parameters in panic disorder and depressive patients. Serotonin (5-HT) levels in blood, platelets and plasma were significantly reduced to 4%, 3% and 28% of their respective baseline values. In addition, the plasma level of tryptophan was also significantly reduced, although the decrease was only 16%. Three months after discontinuation of clomipramine treatment, 5-HT in blood and platelets reached baseline values again, while the plasma 5-HT level was still reduced to 68% of pretreatment values. Unexpectedly, the plasma tryptophan concentration was even lower at this time-point than after six months of treatment. These results show that clomipramine not only has an effect on 5-HT levels in blood, platelets and plasma, but also on plasma tryptophan concentration. We speculate that low plasma tryptophan after treatment may constitute a risk for the recurrence of psychopathology.

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.

Anxiety and autonomic regulation in major depressive disorder: an exploratory study.

Spectral analysis of fluctuations in heart rate and blood pressure was employed to explore sympathetic and parasympathetic cardiovascular control mechanisms in relation to trait anxiety in major depressive disorder Sixteen drug-free female depressed patients were divided into two groups: those who were high on trait anxiety (HTA, n = 9) and those who were normal or low on trait anxiety (LTA, n = 7). In patients and age-matched female controls (n = 10), heart rate (HR), blood pressure (BP; Finapres device) and respiration were recorded during a period of supine rest (10 min), orthostatic challenge (60 degrees head-up tilting, 8 min), and post-orthostatic supine rest (8 min). Power spectra were calculated over the last 4 min of these three situations for HR, systolic BP, as well as for respiration. Spectral density was assessed for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz) and high (0.15-0.50 Hz). Patients did not differ from controls during supine rest. During orthostatic challenge, HTA patients showed significantly more HR increase and suppression of high-frequency fluctuations of HR (suggesting stronger vagal inhibition) in comparison with the controls; this effect was accompanied by a significant increase in respiratory frequency. Both patients groups did not show the normal increase in mid-frequency band fluctuations of BP during orthostatic challenge, indicating reduced sympathetic activation. Low-frequency fluctuations of HR, as well as respiratory frequency during post-orthostatic supine rest of the HTA patients were significantly increased versus controls. This exploratory study indicates that trait anxiety may be a relevant factor when evaluating parasympathetic and sympathetic dysbalances in the state of a major depressive disorder.

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.

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.

Abnormal plasma levels of serine, methionine, and taurine in transient acute polymorphic psychosis.

The present study explored the usefulness of plasma amino acid concentrations in discriminating a subgroup of patients with transient acute polymorphic psychoses characterized by psychosensory symptoms (APP+ patients). Levels of amino acids in the plasma of APP+ patients were compared with levels in psychiatric patients with other types of psychotic symptomatology and a healthy control group. Both the APP+ patients and patients with bipolar affective disorder had significantly lower plasma concentrations of serine compared with concentrations in the other groups studied. Since the plasma concentrations of taurine and methionine were also different in the APP+ patients, the ratio of taurine to the product of serine and methionine (the TSM ratio) was used in an attempt to increase the sensitivity in discriminating these patients. The TSM ratio in the APP+ patients was significantly higher than those in the other groups studied, except for the patients with bipolar affective disorder. It appears that the determination of serine and the TSM ratio in the plasma of psychotic patients may be a useful diagnostic validator in a group of patients with acute polymorphic psychoses.

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.

Serine and glycine-induced catalepsy in porphyric rats: an animal model for psychosis?

It was investigated whether an increased demand for glycine, as postulated to occur in patients who have suffered from episodic psychoses accompanied by multiple perceptual distortions, could evoke psychotic reactions. Catalepsy was used as a measure for psychosis and was observed after injection of serine or glycine in porphyric rats. Catalepsy was was shown to occur after serine as well as glycine administration in 2-allyl-2-isopropylacetamide (AIA) pretreated rats, while in lead (Pb) + phenobarbital pretreated rats only glycine was effective. Administration of AIA to rats resulted in a strongly enhanced excretion of porphobilinogen (PBG) in urine, while Pb + phenobarbital pretreated rats showed increased excretion of delta-aminolevulinic acid (delta-ALA). The Pb + phenobarbital pretreated animals showed elevated serine plasma levels and lowered glycine plasma levels 18 hours after injection, while no significant differences in plasma levels of these amino acids were found 24 hours after AIA administration. In AIA or saline pretreated animals, but not in those pretreated with Pb + phenobarbital, glycine formation from serine was elevated. It is concluded that the present animal model can be used to investigate episodic psychoses.

[The number of admissions to Dutch hospitals for barbiturate poisoning from 1981-1989 and those for poisoning with sedatives and hypnotics,and benzodiazepines]. / Het aantal opnamen in Nederlandse ziekenhuizen voor barbituraatvergiftiging in de periode 1981-1989 en die voor vergiftiging met sedativa en hypnotica, en benzodiazepinen.

Over the period 1981 to 1989, the number of admissions to Dutch general hospitals for barbiturate poisoning has dropped sharply and steadily, due to a more restrictive policy in prescribing regarding these sedatives. This trend is also present concerning poisoning with sedatives and hypnotics in general (ICD-code 967), but not concerning those with benzodiazepines (ICD-code 969.4). The female-male ratio was nearly 2:1. This difference is possibly due to the fact that females take more medication than males.

Trait anxiety, coping with stress, and norharman.

Plasma levels of the beta-carboline norharman, concentration of platelet 5-HT, trait measures of anxiety, and measures of coping and defense mechanisms were compared for 15 patients with panic disorder and 24 healthy volunteers. Patients indicated that they made less use of the defense mechanism of principalization than control subjects. No other differences between patients and controls were significant. Platelet 5-HT concentration was positively correlated with the subjectively reported anxiety. Plasma norharman concentration was negatively correlated with the defense mechanisms of principalization and repression and positively correlated with coping strategies involving palliation. The positive correlations of norharman levels with projection and self-comforting fell short of significance and existed in the patient group only. No correlation was apparent between levels of plasma norharman and scores on anxiety. It was concluded that norharman is not a marker for panic disorder or trait anxiety, but that it might reflect intrapsychic and coping processes.