Biochemical and diagnostic classification and serum drug levels: relation to antidepressive effect of imipramine

The relationship between clinical effect of imipramine (IP) in 39 depressed patients and biochemical distinction, serum drug levels, and diagnostic classification was investigated retrospectively. Based on pretreatment plasma ratios of tryptophan and tyrosine to competing amino acids, which reflect the availability of the precursor amino acids to the brain, the patient sample was separated in two halfparts. The one group with low net availability of tryptophan and tyrosine improved significantly more than the other group with comparable mean serum drug levels. In the former group there was no association between clinical improvement and serum drug levels, whereas in the latter group the patients with serum IP plus desipramine (DMI) above 180 ng/ml improved significantly more than patients with lower levels. There was an indication that a serum ratio of IP:DMI below 0.2 was associated with a poor response. Patients classified as nonendogenous depressives by means of the Newcastle II scale showed about the same response pattern as endogenous depressives with comparable plasma amino acid profiles and serum drug levels. Based on amino acid patterns and serum drug levels only half of the patients received an optimal therapy on the applied schematic dosage schedule. Thus, biochemical classification rather than diagnostic may be a useful remedy for the adjustment of serum IP plus DMI to appropriate levels in individual depressives.     

Nutritional assessment of severely retarded children and adults

The nutritional status was assessed with physical and biochemical parameters on 39 severely retarded children and adults, 17 males and 22 females, ranging from 6 to 40 years of age. In the anthropometric measurements, a majority of the cases showed short stature, light body weight, decreased triceps skinfold thickness and decreased mid-upper arm muscle circumference. The analysis of serum amino acids showed decreases of the sum of essential amino acids, the sum of branched chain amino acids, the ratio of the sum of essential amino acids to the sum of nonessential amino acid, and the ratio of the [methionine + tryptophan] to [valine + lysine + threonine]. The levels of prealbumin and transferrin in the serum were within normal limits. Other biochemical parameters were lower limits, including total protein, albumin, total cholesterol, triglyceride, phospholipid and total lipids in the serum. In addition, the level of fasting blood glucose tended to be low, and levels of serum free fatty acid were markedly different between before and after breakfast. These results suggest the presence of nutritional disturbances in most of severely retarded children and adults.     

Biochemical markers for post-operative fatigue after major surgery

OBJECTIVE: To establish a link between tryptophan (a precursor for 5-hydroxytryptamine (5-HT) or serotonin, involved in sleep and fatigue) and post-operative fatigue after major surgery. BACKGROUND: There is a link between tryptophan (the precursor for the neurotransmitter 5-hydroxytryptamine), and its competitive binding with non-esterified fatty acids (NEFA) to albumin in the blood. An increase in the plasma concentration of free tryptophan can lead to an increased rate of synthesis of 5-HT in the brain. Free tryptophan competes with the branched chain amino acids (BCAA) for the same port of entry across the blood-brain barrier. It is suggested that the plasma concentration of these amino acids could be a marker of post-operative fatigue. In a previous study undertaken in this laboratory on patients undergoing two different types of major surgery, similar post-operative increases were observed in the plasma concentration of free tryptophan and the plasma concentration ratio of free tryptophan to branched chain amino acids. However, the study was retrospective and no measure of fatigue had been made. METHODS: In the present study, this deficiency has been addressed by administering a modified Profile of Mood States questionnaire to patients undergoing reconstructive or colorectal surgery. In addition, blood samples were measured for plasma free tryptophan, albumin, NEFA and branched chain amino acids before and on 2 days after surgery. RESULTS: There was a significant correlation between fatigue scores and plasma free tryptophan (P<0.000), and the plasma concentration ratio of free tryptophan/BCAA (P<0.016) after surgery in all the patients studied (n=34). This correlation was more marked in the colorectal-surgery patients, in whom surgery was more severe. In the three categories of patients receiving elective reconstructive surgery (n=24), those having breast reductions (n=6) had a lower plasma concentration of NEFA and appeared to recover from fatigue more quickly than those with pre-tibial lacerations or malignant melanoma. CONCLUSIONS: These data provide further evidence of a possible biochemical mechanism for central fatigue which involves a precursor of 5-HT. The provision of branched chain amino acids may help to combat the surge in free tryptophan that occurs during stress such as major surgery.     

Effect of various oral protein doses on plasma neutral amino acid levels

Summary Six healthy fasting females each received, on different days, 0, 6, 12.5 or 25 g of albumin dissolved in 200 ml water. Blood was collected before and at intervals after the albumin ingestion and assayed for plasma levels of large, neutral amino acids (LNAA), insulin and glucose. Insulin increased significantly after ingestion of 12.5 and 25 g of albumin, whereas changes in serum glucose were small and inconsistent. Increases of plasma LNAA concentrations were dose-related and correlated significantly with the molar percentage in the albumin of the respective amino acids at 1 and 2 hours but not at 3 and 4 hours after consumption. Ratio in plasma of tyrosine to other LNAA increased by 20 to 60%, and still at 4 hours the plasma tyrosine ratio was significantly elevated above control level after all 3 albumin doses. The plasma ratio of tryptophan to other LNAA decreased by 30 to 50%, and at 4 hours the plasma tryptophan ratio was still significantly below control level after the 2 larger albumin doses. The marked changes in the plasma tryptophan and tyrosine ratio suggests that the central serotonin and catecholamine synthesis could possibly be affected following ingestion of pure protein.     

Serotonergic‘vulnerability’ in affective disorder: a study of the tryptophan depletion test and relationships between peripheral and central serotonin indexes in citalopram-responders

A double-blind study of the tryptophan depletion (TD) challenge was performed on a sample consisting of 20 patients with a major depressive disorder in clinical remission after citalopram treatment. TD was induced by the intake of 43 g of an amino acid mixture containing the five large neutral amino acids. The control group received the same mixture, to which 2.3 g tryptophan had been added. Five of the 12 challenged patients showed a worsening of depressive symptoms during the day of the test. In contrast, there was no mood alteration in the eight control patients. Baseline Cortisol levels were significantly higher in responders to TD compared to those in non-responders and controls. Platelet serotonin-receptor function and plasma prolactin levels were correlated. There was a significant positive correlation in the baseline data between rated mood state and plasma Cortisol and a significant inverse correlation between related mood state and plasma tryptophan concentration. Thus low mood appeared to be associated with low serotonin precursor availability as well as with high Cortisol levels.     

Abnormal amino acid metabolism in patients with early stage Alzheimer dementia

Summary. 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. Accepted February 2, 1998; received November 11, 1997     

Changes in the Albumin Binding of Tryptophan During Postoperative Recovery: A Possible Link With Central Fatigue?

Tryptophan is the precursor of the neurotransmitter 5-hydroxytryptamine (5-HT), known to be involved in sleep and fatigue. In the blood, tryptophan binds to albumin, and that which does not, free tryptophan, competes with branched chain amino acids (BCAA) for entry into the brain. The plasma concentrations of albumin, free tryptophan, total tryptophan, and BCAA were measured before and after major surgery in nine elderly and nine coronary artery bypass graft (CABG) patients. In both the elderly and the CABG patients plasma free tryptophan concentrations were increased after surgery, compared with baseline levels; the plasma free tryptophan/BCAA concentration ratio was also increased significantly after surgery. Plasma albumin concentrations were decreased significantly after surgery in both the elderly and the CABG patients. Plasma BCAA concentrations were not affected by surgery in either group. The effect of exercising to exhaustion on 5-HT and tryptophan were investigated in Nagase analbuminemic rats (NAR). The intrasynaptosomal concentration of tryptophan, 5-hydroxytryptophan, and 5-HT was increased by fatigue after exercise. In addition, running time to exhaustion was shortened in NAR. These data suggest that free tryptophan uptake and 5-HT synthesis were enhanced in the nerve terminal. A decrease in plasma albumin may account for the increase in plasma-free tryptophan levels. An increase in plasma free tryptophan, resulting in an enhanced plasma concentration ratio of free tryptophan/BCAA, may lead to a higher 5-HT concentration in some parts of the brain and, consequently, to central fatigue. It is suggested that provision of BCAA as a dietary supplement may counteract the increase in plasma free tryptophan and thus improve the status of some patients after major surgery.     

Plasma concentrations of amino acids in chronic schizophrenics treated with clozapine.

Peripheral amino acid changes have been reported in schizophrenia, but results are not consistent. We measured serum levels of different amino acids in 11 neuroleptic-resistant schizophrenic patients before and after clozapine treatment and in 11 age- and sex-matched healthy subjects. The schizophrenic patients exhibited significantly higher levels of serum aspartate, glutamate, isoleucine, histidine and tyrosine and significantly lower concentrations of serum asparagine, tryptophan and serine. In patients, the ratio between tryptophan and large neutral amino acids (LNAA) was significantly lower than in matched controls, whereas the tyrosine/LNAA ratio did not differ significantly. Moreover, 12 weeks of clozapine administration significantly reduced serum levels of glutamate but did not restore the values observed in normal controls, nor did it affect other amino acid concentrations. These data show changes in serum amino acids that may influence central serotonergic, dopaminergic and glutamatergic transmission in neuroleptic-resistant schizophrenics.     

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.     

Free tryptophan response to intravenous insulin in depressed patients

Levels of free plasma tryptophan, total plasma tryptophan, and total amino acids were determined at various times after insulin administration in patients with either major depressive disorder or dysthymic disorder and normal control subjects. Prior to insulin administration, there were no significant differences among the three groups in any of the parameters. However, following insulin, free plasma tryptophan levels fell significantly among the patients with major depressive disorder for the first 30 min, but not among normal controls. The rate of decline among the patients with dysthymic disorder was intermediate between those of the patients with major depressive disorder and normal controls. The levels of total tryptophan and amino acids following insulin did not differ significantly among the three groups.     

Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response

Serum total tryptophan and the five competing amino acids (CAA), i.e., valine, leucine, tyrosine, phenylalanine, and isoleucine were determined in 35 major depressed subjects of whom 27 with treatment resistant depression (TRD), and 15 normal controls. Twenty-five of the depressed subjects had repeated measurements of the amino acids both before and after antidepressive treatment. The following immune-inflammatory variables were assayed in the above subjects: serum zinc (Zn), total serum protein (TSP), albumin (Alb), transferrin (Tf), iron (Fe), high-density lipoprotein cholesterol (HDL-C), number of peripheral blood leukocytes, and the CD4⁺/CD8⁺ T cell (T-helper/T-suppressor) ratio. Serum tryptophan and the tryptophan/CAA ratio were significantly lower in major depressed subjects than in normal controls. The tryptophan/CAA ratio was significantly lower in patients with TRD than in patients without TRD and normal controls. There were no significant alterations in any of the amino acids upon successful therapy. There were significant correlations between serum tryptophan and serum Zn, TSP, Alb, Tf, Fe, and HDL-C (all positive), and number of leukocytes and the CD4⁺/CD8⁺ T-cell ratio (all negative). The tryptophan/CAA ratio was significantly and negatively related to the number of leukocytes and the CD4⁺/CD8⁺ T-cell ratio. The results suggest that (a) TRD is characterized by lower availability of serum tryptophan; (b) the availability of tryptophan may remain decreased despite clinical recovery; and (c) the lower availability of tryptophan is probably a marker of the immuneinflammatory response during major depression.     

Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects

Basal serum amino acids (including central monoamine precursors), central monoamines, and hormones were studied in schizophrenic patients (drug-naive; n = 20; drug-withdrawn for 3 or more days, n = 67; neuroleptic-treated, n = 23) and healthy subjects (n = 90) to answer the following questions: (1) Do neuroleptic-withdrawn and neuroleptic-naive patients differ on these serum measures? (2) What are the effects of neuroleptic treatment on these measures? (3) On which variables do drug-free and neuroleptic-treated patients differ? Because serum amino acid, central monoamine, and hormone levels were similar in drug-naive and drug-withdrawn patients, data from these groups ("drug-free") were combined and compared to those of healthy subjects and neuroleptic-treated patients. Asparagine, citrulline, phenylalanine, and cysteine were higher, while tyrosine, tryptophan, and the ratio of tryptophan to competing amino acids were significantly lower in drug-free schizophrenic patients than in healthy subjects. Dopamine was increased, and melatonin and thyroid hormones were decreased in drug-free schizophrenic patients compared to healthy subjects. Norepinephrine, epinephrine, and prolactin were higher in neuroleptic-treated men compared to drug-free male patients or healthy men. These results are consistent with the hypothesis of dopaminergic overactivity in schizophrenia, which might be caused by altered amino acid precursor availability and could be related to the decrease in melatonin and reduction in thyroid hormone levels.     

Inflammation-Induced Catabolism of Tryptophan and Tyrosine in Acute Ischemic Stroke

Whether the inflammatory response that accompanies acute ischemic stroke induces the kynurenine pathway is currently a matter of conjecture. Activation of this pathway may disturb active metabolites. The aim of this study was thus to characterize the catabolism of tryptophan and tyrosine in acute ischemic stroke (AIS) patients, and its association with cytokines, C-reactive protein, and glucose. Serum levels of 5-hydroxytryptamine, tryptophan catabolites, and competing amino acids and significant ratios of these were measured in 45 AIS patients and compared to those of 40 control subjects. Furthermore, associations between the serum levels of these biomarkers and serum levels of cytokines, C-reactive protein, and glucose were determined. Significantly lower levels of tryptophan and tyrosine in the stroke group indicate increased tryptophan and tyrosine oxidation in acute ischemic stroke, while significantly lowered tryptophan index and tyrosine index indicate a reduced capacity for the synthesis of 5-hydroxytryptamine and catecholamines in the brain, respectively. Furthermore, our findings indicate that the proinflammatory response in acute ischemic stroke may be responsible for a reduced capacity for the biosynthesis of brain catecholamines and mediate neurotoxic effects. Meanwhile, the anti-inflammatory IL-10 may exert a neuroprotective effect and prevent the putative reduced capacity for 5-hydroxytryptamine synthesis in the brain. These mechanisms may be involved in several sequelae following stroke, such as cognitive impairment, depression, and fatigue.     

Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies

The plasma amino acid profiles of 36 children with autism spectrum disorders were reviewed to determine the impact of diet on amino acid patterns. Ten of the children were on gluten and casein restricted diets administered by parents, while the other 26 consumed unrestricted diets. No amino acid profile specific to autism was identified. However, children with autism had more essential amino acid deficiencies consistent with poor protein nutrition than an age/gender matched control group. There was a trend for children with autism who were on restricted diets to have an increased prevalence of essential amino acid deficiencies and lower plasma levels of essential acids including the neurotransmitter precursors tyrosine and tryptophan than both controls and children with autism on unrestricted diets. These data indicate that larger, more focused studies of protein nutrition in children with autism are needed in order to determine the extent to which restricted diets might place the developing brains of children with autism at risk from protein malnutrition. The high rate of tryptophan and tyrosine deficiency in this group is also of concern given their role as neurotransmitter precursors.     

Amino acid transport across the human blood-CSF barrier. An evaluation graph for amino acid concentrations in cerebrospinal fluid

The correlation of cerebrospinal fluid (CSF)/serum concentration quotients was used as a method for identification of amino acids which are transported by a common carrier system across the blood-CSF barrier. Isoleucine, leucine, valine, phenylalanine, tyrosine and lysine were found to compete for the same carrier system. This group of amino acids in man was found to be different from the system described as a neutral amino acid carrier at the blood-brain barrier in rats. In man, methionine and tryptophan do not compete with the other neutral amino acids for the same carrier system. In contrast, lysine as a basic amino acid is found to be correlated with the same transport system as the five neutral amino acids. A graph for the evaluation of pathological amino acid concentrations in CSF is presented. Patients with a blood-CSF barrier dysfunction for proteins showed partly normal, partly increased, CSF/serum concentration quotients for the amino acids. Hydroxyproline could be identified as a constituent of the amino acid pool in CSF. For proline and hydroxyproline a special control system has to be suggested because of their smaller biological variance in CSF than in blood. Contrary to the other amino acids proline and hydroxyproline have a smaller biological variation in CSF than in serum.     

Low antioxidant status of serum uric acid,bilirubin and albumin in patients with neuromyelitis optica

Background: Oxidative stress plays a central role in neuropathology of multiple sclerosis (MS). The patients with MS have low antioxidant status. Antioxidant therapy may represent an attractive treatment of MS. However, the relationship between neuromyelitis optica (NMO), a distinct nosologic entity or a form of MS, and antioxidant status has not fully been investigated. Objectives: To investigate the correlation between NMO and serum antioxidant status of uric acid (UA), bilirubin and albumin. Methods: The serum levels of antioxidant molecules UA, bilirubin (Tbil and Ibil) and albumin were measured in 236 individuals comprising healthy subjects and patients with NMO or MS. Results: We found that serum levels of UA, Tbil, Ibil and albumin in patients with NMO were significantly lower than those in healthy control group. Moreover, these results were also observed when the male and female cohorts were investigated separately. Likewise, the serum levels of UA, Tbil, Ibil and albumin in patients with NMO were also lower than those of patients with MS. In all groups, women had lower serum UA, Tbil, Ibil and albumin levels than men. In UA groups, women had significantly lower serum UA levels than men. Conclusion: We concluded that there were reducing serum levels of UA, bilirubin and albumin in patients with NMO. The study showed patients with NMO had low antioxidant status. As a replacement therapy to patients, administration of albumin, bilirubin and UA or theirs precursors, such as inosine of UA precursor, may be beneficial to the patients with NMO.     

Plasma and CSF tryptophan in cancer anorexia

Summary Eighteen untreated cancer patients and ten sex- and age-matched healthy volunteers were studied. In all patients eating behavior was investigated by means of a specific questionnaire from which the presence of anorexia and anorexia-related symptoms was assessed. To investigate the role of tryptophan in cancer anorexia, fasting plasma and CSF levels of tryptophan and other neutral amino acids were assayed in patients and controls.Cancer patients showed abnormally high plasma free tryptophan levels. In case of patients with cancer anorexia a significant rise of the ratio in plasma between free and tryptophan/large neutral amino acids, competing with tryptophan for its brain entry, was observed. This increase was correlated to a consistent rise of CSF tryptophan levels suggesting a specific role of the serotoninergic system in the pathogenesis of cancer anorexia.     

Developmental changes in brain indoles, serum tryptophan and other serum neutral amino acids in the rat

The rates at which brain neurons synthesize and release serotonin depend in part on brain tryptophan concentrations; these, in turn, vary directly with serum (or plasma) tryptophan, and inversely with the serum concentrations of other large neutral amino acids (LNAA). Concentrations of serum tryptophan, LNAA and brain indoles were examined in samples drawn at noontime from rats aged 0-59 days. Developmental changes in serum tryptophan largely paralleled those in the tryptophan/LNAA ratio, and brain tryptophan concentrations. Brain serotonin and 5-hydroxyindole acetic acid (5-HIAA) levels also increased postnatally; the changes in 5-HIAA tended to parallel those in brain tryptophan while those in serotonin did not.     

Serotonin metabolism in human epiepsy: The influence of anticonvulsant drugs

Cerebrospinal fluid levels of tryptophan, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) were measured in 26 untreated and 46 treated epileptic patients and 32 neurological controls. Levels of these substances were normal in the untreated epileptic patiens, but elevated CSF tryptophan and a trend toward elevation of 5-HIAA were found in the treated group. The rise in CSF tryptophan and 5-HIAA appeared related to the number of anticonvulsants administered and the serum levels of phenobarbital and diphenylhydantoin. Particularly high values were seen in anticonvulsant-intoxicated patients. There was no significant correlation between CSF levels of tryptophan and 5-HIAA in control and untreated patients, but a positive correlation was found in the treated group. The slight rise in CSF levels of HVA in treated epileptic patients was not significant, but a positive correlation was found between CSF levels of 5-HIAA and HVA.     

Effect of excess intracranial amino acids on memory: a behavioural survey

Nineteen naturally occurring amino acids were administered intracranially to day-old chicks at various times before and after a single trial passive avoidance learning task. The results suggest a consistent and simple difference between essential and non-essential amino acids. Except for arginine, phenylalanine, tryptophan and tyrosine, the essential amino acids had no effect on memory formation when administered 5 min before or immediately after learning. However, arginine, phenylalanine and tryptophan yielded amnesia after 60 min following learning, when given between 5 min before and 2.5 min after learning. In the case of tryptophan, amnesia was only temporary, lasting from 60 min to 240 min post-learning. All non-essential amino acids, when administered between 5 min before and 5 min after learning yielded amnesia by 60 min post-learning, with no evidence of recovery by 24 hr post-learning. Alanine-, asparagine-, cysteine- and glutamate-treated chicks, however, showed signs of generalized avoidance shortly after administration. The retention time courses after injection of glutamine, proline, serine and taurine were similar to that obtained with the non-metabolizable amino acid alpha-amino-isobutyric acid, and amnesia arising from administration of these amino acids was counteracted by diphenylhydantoin, as was amnesia induced by phenylalanine and tyrosine. The retention function obtained with tryptophan was similar to that obtained with 5-hydroxytryptamine, and DPH had no effect on the action of tryptophan or the actions of arginine, alanine or asparagine. The findings were interpreted in the context of a three-stage model of memory formation.(ABSTRACT TRUNCATED AT 250 WORDS)