Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated. Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized from L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission. In the present study, markedly increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia) independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN. Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus, particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and IgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation. We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease. In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.
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PMID:Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. 142 88

Because of the limitations in efficacy and safety of the older tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI) a number of new approaches have been made in recent years to the treatment of depression to obtain more effective, more rapidly acting, better tolerated and safer drugs. One tactic has been to develop compounds with greater neuropharmacological selectivity in inhibiting the neuronal reuptake of 5-HT. Most of these are as effective as TCA but with fewer side-effects and greater safety. Another development has been 'reversible' MAOI which reduce the risk of interaction with tyramine-containing foods. For resistant depression the addition of lithium (and/or tryptophan) may be effective, possibly through promoting 5-HT neurotransmission. Continuous treatment with a selective 5-HT reuptake inhibitor can reduce the relapse rate in patients with recurrent depression. Unfortunately, these new approaches, despite their advantages in terms of side-effects and safety, have thus far not proved to be more effective or faster acting than the standard TCA. That remains a challenge for the future.
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PMID:New aspects in the treatment of depression. 143 Oct 20

At least three categories of atypical depression have been described. The hysteroid dysphoria is characterized by repeated episodes of depressed mood in response to feeling rejected, and a craving for sweets and chocolate. Two other issues are characterized by a cyclical occurrence of changes of mood and appetite, i.e., the late luteal phase dysphoric disorder (DSM-III-R, appendix), or "the premenstrual syndrome" (PMS), and the major depression with seasonal pattern (DSM-III-R), or seasonal affective disorder (SAD). The reactive mood changes are frequently accompanied by features as hypersomnia, lethargy and increased appetite, particularly with a preference for carbohydrates. Central serotonin pathways participate in the regulation of mood and behavioural impulsivity, and modulate eating patterns qualitatively and quantitatively. Depressives with PMS og SAD benefit, in general, from treatments with serotonin potentiating drugs, suggesting that brain serotonin plays a role in the pathophysiology. Ingestion of carbohydrates increases the plasma ratio of tryptophan to other large neutral amino acids in man and animal, and the serotonin synthesis in the rat brain. Based on these findings it has been suggested that the excessive carbohydrate intake by patients with PMS and SAD reflects a self-medication that temporarily relieves the vegetative symptoms via an increased central serotonergic activity.
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PMID:Serotonin, carbohydrates, and atypical depression. 148 May 61

In a previous paper evidence was presented to show that Helicobacter-induced chronic gastritis is the probable cause of most chronic hypochlorhydria. In this article evidence is presented for the clinical relevance of reduced stomach acid secretion. Reduced mineral absorption is fairly well documented and has sound theoretical support from basic chemistry. Impaired digestion of protein has been suggested by a few studies. Small intestinal bacterial overgrowth in hypochlorhydria probably leads to putrefactive breakdown of the metobolically useful products of protein digestion, thereby reducing their availability for certain essential pathways. The possible lowering of tryptophan, tyrosine, and phenylalanine in the blood may be a precipitating factor in depression in hypochlorhydric patients. In reduced or absent stomach acid secretion a constellation of gastrointestinal symptoms has been consistently observed and reported by clinicians in the past, and treatment of the hypochlorhydria with hydrochloric acid or its substitutes has often been observed to be effective in reducing these symptoms.
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PMID:The clinical importance of hypochlorhydria (a consequence of chronic Helicobacter infection): its possible etiological role in mineral and amino acid malabsorption, depression, and other syndromes. 149 27

The authors briefly review studies of the efficacy of potent serotonin reuptake inhibitors (SRIs) (e.g., clomipramine, fluvoxamine) in obsessive compulsive disorder (OCD) and compare the use of antidepressants in the treatment of depression and OCD. They propose an algorithm for those patients with OCD who fail to respond to an adequate trial with a potent SRI and discuss the promise and limitations of adding tryptophan, fenfluramine, lithium, buspirone, or a neuroleptic to ongoing SRI therapy. Other biological approaches (e.g., ECT, psychosurgery) are considered in terms of their narrowly defined roles in the treatment of patients with SRI-resistant OCD.
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PMID:Pharmacotherapy of obsessive compulsive disorder. 153 62

The possible role of amino acid availability and a functional hypothalamic-pituitary-adrenal axis in the mood disturbances often reported in postpartum women and in users of the oral contraceptive was examined by measuring amino acids and doing a dexamethasone suppression test. Plasma cortisol, tryptophan, tyrosine, their competing amino acids in brain uptake (CAA), and the effect of 1mg dexamethasone were determined in 10 women taking oral contraceptives, 31 women 3 days postpartum, and 9 controls. The pill contained 30 mcg ethinyl estradiol and .075 mg gestodene (2 women), and 30 mg ethinyl estradiol and .15 mg desogestrel (8 women). The subject also took self-rating mood scales: Zung Depression, Zung Anxiety, Beck Depression and State Anxiety Inventory. Cortisol was significantly higher in postpartum women and pill users than in normal controls. Tryptophan, valine, isoleucine and leucine were lower in postpartum women. Tyrosine and tyrosine CAA were lower in postpartum women and pill users. 80% of the postpartum group had negative dexamethasone suppression tests, i.e., cortisol 5 mcg/dl 24 hours after 1 mg dexamethasone. After dexamethasone valine was significantly higher and tryptophan/CAA and tyrosine/CAA ratios were lower, as a result of slightly lower tryptophan and tyrosine and slightly higher CAAs. Furthermore, effects on the amino acid ratios were only evident in women exhibiting dexamethasone suppression. There was a significant negative correlation between depression and anxiety scores and the tryptophan/CAA ratio. The results indicated first that the dexamethasone suppression test is an invalid marker for major depression, and also that availability of the amino acid precursors of brain neurotransmitters may affect mood in the puerperium.
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PMID:Disturbances in dexamethasone suppression test and lower availability of L-tryptophan and tyrosine in early puerperium and in women under contraceptive therapy. 156 Apr 30

A patient suffering from endogenous depression was treated with mianserin and developed agranulocytosis. After recovering from this, and with the depression in remission, the patient was given L-tryptophan. When this medication was removed from the market, due to the newly described eosinophilia-myalgia syndrome, a change was made to oxitriptan, which then caused a serious asymptomatic eosinophilia. No similar cases have yet been reported. Following withdrawal of oxitriptan, the eosinophilia disappeared. Evidence for any other cause of the condition was not found. Causes and physiopathology of drug-induced agranulocytosis and eosinophilia and the circumstances of such complications following use of mianserin and oxitriptan are discussed.
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PMID:[Mianserin agranulocytosis followed by oxitriptan eosinophilia]. 160 92

In this study, we have measured the following biological variables in 78 depressed inpatients: adrenocorticotrophic hormone (ACTH) responses to corticotropin releasing factor (CRH: 100 micrograms intravenously), postdexamethasone cortisol and ACTH values, and circulating concentrations of L-tryptophan (L-TRP). Patients were categorized according to the DMS-III as (1) minor depression, (2) simple major depression, and (3) major depression with melancholia/psychotic features. By means of various pattern recognition methods, we determined whether these diagnostic groups constitute discrete biological classes or form relevant stages (i.e., continuous categories) in a continuum of progressing biological dysfunction. We established that unipolar depression constitutes one biological continuum characterized by a progression of lower CRH-induced ACTH responses, lower L-TRP levels, and higher postdexamethasone cortisol and ACTH values along the diagnostic spectrum. However, the biological differences in these markers between melancholia and minor depression are quantitatively prominent to the extent that they become qualitative. These findings support the biological heterogeneity hypothesis of melancholia. Simple major depression is a heterogeneous class with regard to the biological markers employed.
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PMID:Biological heterogeneity of melancholia: results of pattern recognition methods. 165 16

The addition of lithium to the tricyclic antidepressant medication of 23 patients with major depression resulted in an increase in the prolactin response to intravenous L-tryptophan after both four days and four weeks of treatment. The extent of this increase did not distinguish the ten patients who were classified as clinical responders (greater than 50% reduction in score on the HRSD). Among the responders there was a modestly significant correlation between the decrease in score on the HRSD and the enhancement of tryptophan-induced prolactin release. Some responders, however, showed very little change in this endocrine response over the four weeks of lithium treatment. Lithium may increase brain 5-HT function in tricyclic-resistant depression but there is only limited support for the hypothesis that changes in brain 5-HT function are involved in the antidepressant effect of this treatment combination.
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PMID:Lithium in tricyclic-resistant depression. Correlation of increased brain 5-HT function with clinical outcome. 165 18

Several developments in serotonin neuropharmacology have implications for psychiatric disorders and have already begun to impact their treatment. Selective inhibitors of serotonin uptake, which enhance serotonergic function by preventing the removal of serotonin from the synaptic cleft via the membrane transporter, have been introduced for the treatment of depression and may be effective in other disorders. Precursor loading can increase serotonin concentrations in the synaptic cleft, and tryptophan--which has been available in health food stores and drug stores--had become increasingly used for self-medication of depression, insomnia, and premenstrual syndrome. Conversion to serotonin is not the major metabolic pathway for tryptophan, and large increases in other tryptophan metabolites (such as quinolinic acid, a substance that is excitotoxic at high concentrations) accompany small increases in extracellular serotonin. The recent epidemic of the eosinophilia-myalgia syndrome associated with tryptophan now appears due to a trace contaminant in the product from a single manufacturer. A major advance in serotonin pharmacology has been the elucidation of serotonin receptor heterogeneity. At least seven receptor subtypes (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) have been identified in brain. Direct-acting agonists and antagonists can have selective affinity for specific receptor subtypes. Selective activation of 5-HT1A receptors seems to cause anxiolytic and possibly antidepressive effects. Selective antagonists of 5-HT2 or 5-HT3 receptors may be useful in treating anxiety and schizophrenia. Drugs that enhance serotonergic function suppress aggression in animals, but the specific receptor subtypes involved are not known. The advances being made in serotonin pharmacology will help define the role of this brain neurotransmitter in psychiatric and other disorders and can be expected to lead to further therapeutic advances.
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PMID:Role of serotonin in therapy of depression and related disorders. 167 51


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