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)

The hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in many patients with depression, probably at all levels of the axis. To determine if HPA dysregulation is associated with severity of depression, we studied a group of 66 patients with major depressive disorder. Each patient underwent a pretreatment Dexamethasone Suppression Test, with plasma postdexamethasone cortisol determination at 8:00 AM, 4:00 PM, and 11:00 PM. All three postdexamethasone cortisol levels were significantly correlated with the Hamilton Rating Scale for Depression (HRSD) scores. We also examined the "profile" measures of mean, maximum, and minimum of the three cortisol values; again, all three were significantly correlated with HRSD scores. To evaluate associations between clinical severity and HPA dysregulation at the pituitary level, we studied a second group of 44 patients with major depressive disorder. Each had postdexamethasone cortisol determinations at 4:00 PM and 11:00 PM as well as pre- and postdexamethasone beta-endorphin determinations at 4:00 PM. The cortisol data from this group followed the same pattern as in the first sample, and there was a significant relationship between HRSD score and degree of beta-endorphin nonsuppression as well. These results suggest that severity of depression is one of the determinants of dysregulation at both adrenal and pituitary levels of the HPA axis, accounting for 10%-20% of the observed variance.
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PMID:Postdexamethasone plasma cortisol and beta-endorphin levels in depression: relationship to severity of illness. 295 96

A family history of depression (but no alcoholism), a history of bipolarity, and a history of nonsuppressor status on the Dexamethasone Suppression Test (DST) have all been positively associated with each other in previous studies. We divided depressives into three mutually exclusive groups, using the three historical parameters described above. Group A included those who were nonsuppressors at index. Group B included normal suppressors at index who met one of the following three criteria: (1) past history of a nonsuppressing DST, (2) past history of a mania, and (3) family history of depression (but no alcoholism). The remaining suppressors at index made up Group C. We found that Groups A and B show a phase advance (an earlier nadir) in the predexamethasone circadian curve for cortisol. Adrenocorticotrophic hormone (ACTH) varies in part (but not solely) with cortisol and may separate the groups.
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PMID:The relationships of historically defined subtypes of depression to ACTH and cortisol levels in depression: preliminary study. 298 56

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest that serotonergic neurons may play a role in the pathophysiology, as well as mediating the pharmacological reduction, of obsessional symptoms.
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PMID:Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology. 303 59

The present study examined the interactions of the synthetic glucocorticoid, dexamethasone, with the regulation of chick intestinal calbindin-D28K (a 28,000 Da vitamin D-dependent calcium binding protein, CaBP) and its mRNA by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Dexamethasone (0-500 nmol) had a neutral impact on calbindin levels in the rachitic chick intestine when measured 12 h later. However, dexamethasone appeared to exert a significant, though modest, stimulatory influence upon calbindin-mRNA accumulation in the vitamin D-deficient (-D) intestine when measured 12 h after administration. 1,25(OH)2D3 also stimulated calbindin-mRNA accumulation in the -D chick intestine; half-maximal (ED50) doses were 1.1 nmol (7.6-fold) and 12.6 nmol (4.3-fold stimulation) for 1,25(OH)2D3 and dexamethasone respectively. In contrast, when both 1,25(OH)2D3 and dexamethasone were administered simultaneously, the stimulatory effect of 1,25(OH)2D3 (and that of the glucocorticoid) was lost in terms of calbindin and calbindin-mRNA accumulation. Dexamethasone treatment of vitamin D-replete (+D) chicks resulted in a depression of calbindin-mRNA accumulation; levels were depressed to baseline with 250 nmol/bird. Dexamethasone (1.25 mumol per day for 3 days) also induced an apparent 'down-regulation' of the 1,25(OH)2D3 receptor population in the -D chick intestine but failed to influence the binding of 1,25(OH)2D3 to its receptor in vitro. Taken collectively, these data indicate that glucocorticoids are able to influence the receptor-mediated action of 1,25(OH)2D3, possibly at the level of calbindin-D28K gene expression.
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PMID:Inhibitory and stimulatory effects of dexamethasone and 1,25-dihydroxyvitamin D3 on chick intestinal calbindin-D28K and its mRNA. 303 23

The aims of the present study were to investigate the value of adding DSM-III diagnosis and Newcastle Scale Rating to the ICD-8 diagnosis currently used and to investigate the association between Dexamethasone Suppression Test (DST) and the Thyrotropine Releasing Hormone- Thyroid Stimulating Hormone (TRH-TSH) test and the three classification systems for depression. Twenty-six depressed in-patients were included, 17 women and 9 men, with a mean age of 51.5 years. Fourteen patients were psychotic depressed. DST and Newcastle Scale Rating were performed on 18 patients and TRH-TSH test was performed on 16 patients. The addition of DSM-III diagnosis on the 4-digit level did not have any value compared to the ICD-8 diagnosis. However, DSM-III diagnosis on the 5-digit level added important clinical information which corresponded better to Newcastle Scale scores and DST and TRH-TSH test results than ICD-8 diagnosis. The main advantage of the DSM-III classification of depression on the 5-digit level compared to ICD-8 concerns depression on the border between psychosis and neurosis. In clinical practice there is a risk of underestimating the severity of a depression if ICD-8/9 is used as the only criterion for severity. This may have tragic consequences for the patient. This study suggests that rating of the depression on the Newcastle Scale or provision of a DSM-III diagnosis on the 5-digit level are valuable assessment procedures of severity.
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PMID:A comparison of DSM-III and ICD-8 diagnoses for major affective disorders and the use of biological markers for depression. 309 84

The antidepressive properties of the specific serotonin reuptake inhibitor fluvoxamine and the specific norepinephrine reuptake inhibitor oxaprotiline were investigated in a sequential design with the aim of evaluating the hypothesis that two distinct biochemical subtypes of depression exist. Responders were treated for 7 weeks with the compound to which they had responded. After 1 placebo week, the nonresponders were switched to the alternative compound. An evaluation of the data obtained during the 3-week treatment periods from 24 patients (37 trials) with major depression revealed a highly significant reduction of Hamilton Scores with both compounds, oxaprotiline and fluvoxamine. If the patients with major depression are subdivided into two groups, endogenous depressives and neurotic depressives, there is no significant difference between the therapeutic improvements (both compounds) achieved in the two groups. The data shows that only about 20% of the nonresponders on one compound responded to the alternative drug, whereas 90% of responders (within 3 weeks) were still responders after 7 weeks. The data are at variance with the concept of two distinct biochemical subtypes of depression (serotonergic vs. norepinephrinergic). Dexamethasone suppression tests, performed in 23 patients, gave no prognostic hint as to whether the patients reacted well to drug therapy or not.
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PMID:Serotonin reuptake inhibition vs. norepinephrine reuptake inhibition: a double-blind differential-therapeutic study with fluvoxamine and oxaprotiline in endogenous and neurotic depressives. 310 9

It has been suggested that dexamethasone pharmacokinetics may affect cortisol suppression during the Dexamethasone Suppression Test (DST). In depressed patients the cortisol response has been shown to negatively correlate with dexamethasone plasma concentrations, which also influence the sensitivity and specificity of the DST. These findings have been interpreted as weakening the utility of the DST. However, the analysis of pre- and post-1 mg DST cortisol concentrations corrected for plasma dexamethasone concentrations suggest that compared with normals (n = 52), patients with major depressive disorder (MDD) as a group (n = 71) had less suppressibility of cortisol to the same plasma dexamethasone concentrations. Moreover, when the MDD patients were evaluated based on DST status, the suppressors had cortisol/dexamethasone ratios (micrograms/dl of cortisol per ng/ml of plasma dexamethasone) similar to the normal controls, whereas the nonsuppressors had ratios that were significantly higher. These data suggest that DST non-suppression, as well as sensitivity and specificity of the DST in depression, is not only attributable to altered dexamethasone disposition, but indeed, there is a genuine reduced sensitivity of cortisol to dexamethasone that still points to an abnormality of the delayed feedback mechanism of the hypothalamic-pituitary-adrenal system in some depressed patients.
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PMID:Cortisol suppression per nanogram per milliliter of plasma dexamethasone in depressive and normal subjects. 316 45

The effect of in vivo (1 mg) and in vitro (10(-7)-10(-10) M) dexamethasone administration on mitogen-induced lymphocyte proliferation was examined in drug-free depressed patients, nondepressed psychiatric patients, as well as normal controls, and was related to the results of a standard overnight Dexamethasone Suppression Test (DST). The effect of oral dexamethasone administration was also examined for its effect on lymphocyte cytosolic glucocorticoid receptor content. Oral dexamethasone administration significantly decreased both phytohemagglutinin (PHA) and concanavalin A (Con-A) induced lymphocyte proliferation, as well as glucocorticoid receptor number in suppressors, whereas dexamethasone failed to decrease these responses in nonsuppressors. Nonsuppressors had significantly lower serum dexamethasone levels compared to suppressors at both 8:00 AM and 4:00 PM. However, when differences in serum dexamethasone levels were covaried out, there were still significant differences between suppressors and nonsuppressors on the dexamethasone-induced mitogen changes, but the changes in glucocorticoid receptor content were no longer significant. In vitro incubation of lymphocytes with dexamethasone produced a dose-related decrease in mitogenesis, which was not different between the depressed and nondepressed groups. However, at physiologically relevant concentrations of dexamethasone (10(-9)-10(-10) M), nonsuppressors as compared to suppressors were more resistant to the immunosuppressive effects of in vitro dexamethasone on the Con-A response. The inhibitory effect of in vitro dexamethasone on Con-A-stimulated lymphocytes was positively correlated with basal 4:00 PM cortisol values. In conclusion, in vitro techniques are useful probes to assess glucocorticoid sensitivity in depression. The present results also further support the hypothesis that glucocorticoid insensitivity is associated with DST nonsuppression.
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PMID:Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppression test. 326 79

Mice bearing the S-180 sarcoma displayed a depression of liver catalase and cytochrome P-450-dependent enzymes (ethoxycoumarin deethylase, ED) from day 6 following tumor implantation. Injection of serum obtained from tumor-bearing mice into normal mice caused depression of liver ED suggesting that a circulating factor was involved. Tumor-bearing mice did not show any significant change in serum triglycerides and food intake. By contrast, injection of endotoxin, interleukin-1 (IL-1) or tumor necrosis factor (TNF) caused not only a depression in liver ED but also a marked increase in serum triglycerides. To study the possible analogies between cancer-associated circulating factor and monokines, we studied the effect of dexamethasone (a known inhibitor of monokine synthesis) on liver ED activity in tumor-bearing mice. Dexamethasone (DEX) treatment increased (up to 60%) liver ED activity in tumor-bearing mice. We conclude that: (i) a circulating factor is involved in cancer-associated ED depression; (ii) that this mediator is not necessarily identical to TNF or IL-1 and (iii) that DEX reverses the depression of liver ED in cancer, possibly by inhibiting the synthesis, or the effects, of this factor.
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PMID:Depression of liver drug metabolism in sarcoma-bearing mice. Evidence for a circulating factor and dissociation from lipolytic activity. 326 84

Life-threatening increased intracranial pressure can be reversed by a variety of drugs. These compounds all have some disadvantages, producing rebound effects, severe coma or cardiovascular depression and electrolyte imbalance. However, reduction of intracranial pressure is a prerequisite for recovery and the benefits of treatment outweigh the risks. Dexamethasone is rapidly eliminated, the short half-life (about 3 hours) indicating that dosage intervals should be kept small. As yet, however, its therapeutic efficacy has not been clearly demonstrated. Therefore, an association between pharmacokinetics and pharmacodynamics cannot be established. Osmotic diuretics are the most widely used agents for reduction of intracranial pressure. Pharmacokinetics show a very close relationship to changes in serum osmolality, but there are large variations in the clearance. For the use of osmotics, the blood-brain barrier must be intact. Osmotic diuretics may lead to intracerebral oedema or to acute renal failure as serum osmolality increases. Considering the pharmacokinetics of each drug, and the dynamics of intracerebral pressure and osmolality, an intermittent, individually titrated dosage should be administered, with simultaneous monitoring of intracranial pressure. Frusemide (furosemide) can be used as an adjunct, to enhance the effect of osmotic diuretics. Its pharmacokinetics are limited by renal function, depending on age as well as on the extent of renal impairment. Altered renal elimination of concomitantly administered drugs, and electrolyte imbalances should be anticipated when diuretics are used. Barbiturates are certain to decrease intracranial pressure in humans by an as yet unknown mechanism. Their administration is recommended for patients that do not respond to conventional therapy. As barbiturates can result in deep coma, knowledge of their pharmacokinetics is of great importance for recovery. Following single doses, pentobarbitone has a relatively long elimination half-life (about 22 hours). However, after repeated administration for several days, its elimination may be enhanced due to autoinduction. Thiopentone kinetics are characterised by distribution and redistribution into deep peripheral compartments. Administration of high and frequent doses leads to considerably delayed recovery. This is not true for methohexitone, which shows comparable pharmacokinetics after single and multiple dose administration. Elimination depends on liver blood flow. Thus, recovery from methohexitone-coma is rapid. Rapid elimination is also an important characteristic of etomidate and alphaxalone/alphadolone, two non-barbiturate hypnotics.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Clinical pharmacokinetic considerations in the treatment of increased intracranial pressure. 330 68


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