Spontaneous plasma cortisol was measured in the interval from 15.00-18.00 h 74 hospitalized depressed patients (56 endogenously and 18 non-endogenously depressed according to the Newcastle index). The cortisol value at the individual time points correlated well with the mean cortisol concentration with the best correlation in the interval between 16.00 and 17.00 h (RHO = 0.89-0.92). For most patients maximum cortisol concentration was found early in the sampling period. Plasma cortisol was high during depression and was reduced after recovery in both diagnostic groups. Correlation between plasma cortisol during depression and type of depression or degree of depression was poor indicating that spontaneous plasma cortisol might have only a limited diagnostic value. However, among the endogenously depressed patients those not responding to treatment with cyclic antidepressants alone had significantly higher cortisol levels prior to treatment than responders. Afternoon plasma cortisol thus may be used as a predictor of the outcome of treatment with cyclic antidepressants.

Adolescent↗

PubMedDate not supplied

Afternoon cortisol levels before (spontaneous) and after suppression with dexamethasone or oxazepam in depressed patients.

In 35 hospitalized depressed patients afternoon plasma cortisol (15:00-15:20 h) was measured in 3 ways: spontaneous, 2 h after administration of 45 mg oxazepam, and 16 h after administration of 2 mg dexamethasone. Dexamethasone and oxazepam caused a marked suppression of cortisol secretion, the former being the most pronounced. A significant correlation between spontaneous and suppressed cortisol levels was found and a correlation between the suppressed cortisol levels was also demonstrated. Both spontaneous and suppressed cortisol values correlated with measures of type (Newcastle scales) and severity (Hamilton rating scale) of depression, and the highest correlations were obtained with cortisol values after dexamethasone suppression. Analysis of the items of the Hamilton rating scale for depression showed a high correlation with retardation (items 7 + 8) and somatic complaints (items 12 + 13). A high correlation with the items 8 + 9 + 10 + 12, as found in an earlier study, was also found in this study. On the basis of these findings it is concluded that hypersecretion of cortisol measured spontaneously or after suppression is not a true diagnostic measure (within a group of depressed patients), but reflects differences in the intensity of certain psychiatric symptoms constituting the depressive syndrome.

Adult↗

PubMedDate not supplied

The cortisol suppressing effect of dexamethasone and oxazepam in depressed patients; significance of spontaneous levels and interindividual distribution.

In 72 hospitalized depressed patients afternoon plasma cortisol (15.00-15.20) was measured in three ways: spontaneous (n = 72), 16 h after administration of 2 mg dexamethasone (n = 71) and 2 h after administration of 45 mg oxazepam (n = 28) or 60 mg oxazepam (n = 37). When cortisol values were log-transformed the histograms and probit functions of spontaneous cortisol levels and cortisol levels after oxazepam suppression suggested log-normal distributions. However, for cortisol levels after suppression with dexamethasone the probit function was sigmoidal, suggesting non-normality. In addition the histogram for this parameter had two peaks. The most pronounced suppression with dexamethasone was obtained in patients with low spontaneous cortisol levels. In contrast the somewhat weaker cortisol suppressing effect of 45 or 60 mg oxazepam appeared not to be influenced by the spontaneous cortisol level.

Adult↗

PubMedDate not supplied

The Diagnostic Melancholia Scale (DMS): dimensions of endogenous and reactive depression with relationship to the Newcastle Scales.

The two diagnostic Newcastle Scales for depression have been evaluated in a drug trial with antidepressants. By use of latent structure analysis (Rasch models) it was found that two dimensions are necessary for describing the diagnosis of depression, one for endogenous features and one for reactive features. Of the depressed patients 50% had a pure endogenous depression, 14% had a pure reactive depression, 32% had mixed endogenous and reactive depression, and 4% had uncertain diagnosis. In the pure endogenous depression group 77% had a monotonically non-decreasing improvement curve during treatment whereas in the other diagnostic categories around 50% had such an improvement.

Adjustment Disorders↗

PubMedDate not supplied

Effects of imipramine of the orthostatic changes in blood pressure, heart rate and plasma catecholamines.

The effect of imipramine on the orthostatic changes in heart rate, blood pressure and plasma catecholamines were examined in six healthy male subjects on two occasions on high sodium balance (Na+ excretion greater than 120 mmol per day) and on low sodium balance (Na+ excretion less than 110 mmol per day), respectively. Orthostatic tests were carried out before and 2 h after ingestion of 150 mg imipramine hydrochloride. Imipramine caused a moderate increase in supine systolic blood pressure, and a pronounced increase in the rise in heart rate, when the subjects assumed erect position. The orthostatic drop in systolic blood pressure was in most cases only moderately increased after ingestion of imipramine, but in three subjects pronounced orthostatic hypotension developed when the sodium balance was low, whereas no clinical symptoms were seen in the same subjects when tested after imipramine ingestion on a high sodium balance. The plasma catecholamine levels in supine and standing position were not influenced by imipramine or by the changes in sodium balance. The data may suggest that inhibition of presynaptic reuptake of noradrenaline and/or alpha 2-adrenoceptor blockade causes the moderate rise in supine blood pressure, whereas alpha 1-adrenoceptor blockade, mainly affecting the venous part of the vascular bed, may explain the orthostatic reactions.

Adrenergic alpha-Antagonists↗

PubMedDate not supplied

Plasma level monitoring of tricyclic antidepressant therapy.

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Amitriptyline↗

PubMedDate not supplied

Plasma concentration and clinical effect in imipramine treatment of childhood enuresis.

The relationship between steady-state plasma concentraton and clinical effect of imipramine in the treatment of nocturnal enuresis was studied in 22 hospitalised children. After 1 week on placebo the children were given imipramine in a fixed dose of about 1 mg/kg for 3 weeks. The enuresis frequency decreased significantly from the placebo to the first week on imipramine, but then no further improvement was observed. There was a significant correlation between steady-state plasma concentration of desipramine or imipramine + desipramine and the reduction in enuresis frequency during imipramine treatment. The optimum effect was obtained when steady-state levels of imipramine + desipramine were above 60 microgram/L; i.e. the effective concentration in enuresis is 3 to 4 times lower than in antidepressive therapy. Dose- and weight-corrected, steady-state plasma concentration of imipramine and desipramine were not significantly different from those previously observed in younger adults. In 1 child, a transient rise in imipramine and desipramine concentration was seen during a period with fever and bacterial infection.

Adolescent↗

PubMedDate not supplied

[Concept of 2nd generation antidepressive agents].

Since the discovery of imipramine and iproniazide, the tricyclic antidepressants (TCA) have maintained a significant role in the pharmacotherapy of depression, whereas the MAO-inhibitors play a minor role because of toxicity problems. However, even the tricyclics present problems and the research to obtain a new "second generation" of less toxic and more efficacious antidepressants have been fully justified. This research has been based on biological models of depression and/or the experimental effects of existing antidepressants. In spite of the considerable investments over 30 years, the validity of prevailing biological depression-models is uncertain. Among the experimental effects of existing antidepressants, their ability to inhibit the reuptake of noradrenaline and serotonin has attracted most attention, resulting in the development of very selective compounds. Likewise, new selective and in particular reversible MAO-inhibitors have been developed. In light of the doubious validity of the experimental models, the clinical testing remains the crucial point. However, clinical trial methodology poses a number of problems, and there is much uncertainty concerning the efficacy of the heterogenous group of "second generation" antidepressants. Therefore, they are generally considered as antidepressants of second choice.

Antidepressive Agents↗

PubMedDate not supplied

[Role of pharmacogenetics in psychopharmacotherapy].

Genetic polymorphism related to certain P450 isozymes, in particular the sparteine/debrisoquine oxygenase, is the dominant cause of interindividual variation in elimination of several drugs. If the pharmacokinetic variability is large, relative to the therapeutic index of the drug, the genetic polymorphism will be clinically important. If the dose cannot be adjusted on the basis of effect measurements, phenotyping may be a supplement or replacement for drug level monitoring which is otherwise relevant for such drugs. Several aspects as elucidated by the experience with the sparteine/debrisoquine oxidation polymorphism ought to be analysed: The role of active metabolites and their rate of formation and elimination, selective drug-drug interaction at the polymorphic isozyme or at alternative routes of elimination, the possible role of two or more polymorphic drug oxidation pathways, and the effect of saturable kinetics. The sparteine/debrisoquine oxidation polymorphism affects two major classes of drugs in psychopharmacology, the antidepressants and the neuroleptics, and this is the best example of clinical relevance of pharmacogenetic polymorphism. Routine use of phenotyping thus should be considered for psychiatry departments.

Antidepressive Agents↗

PubMedDate not supplied

In vitro evidence against the oxidation of quinidine by the sparteine/debrisoquine monooxygenase of human liver.

Competitive inhibition studies using human liver microsomes have shown that quinidine (QD) has an exceptionally high affinity (60 nM) for the genetically variable cytochrome P-450 that catalyzes the formation of 4-hydroxydebrisoquine and dehydrosparteines from debrisoquine and sparteine. The present study examined the effect of sparteine and debrisoquine on the oxidation of QD by microsomes prepared from two human livers. QD and its major metabolite 3-hydroxy-QD were measured by quantitative TLC. QD 3-hydroxylation followed saturable single-site kinetics over a 1-250 microM range of QD concentrations. The Km and Vmax of the reaction in the two liver specimens were 47.5 +/- 3.5 microM and 58.7 +/- 5.9 microM, and 0.36 +/- 0.08 and 0.29 +/- 0.02 nmol of 3-hydroxy-QD/mg of protein/min. Sparteine and debrisoquine (250 microM) had no effect on this QD 3-hydroxylase activity. Furthermore, near-saturation of the sparteine/debrisoquine isozyme by 250 microM sparteine had no effect on the oxidation of QD by all routes (measured by QD disappearance from an initial level of 70 nM during an 8-hr incubation period). These observations indicate that none of the major oxidative reactions of QD are catalyzed by the sparteine/debrisoquine isozyme; QD may simply bind to this cytochrome P-450, without being oxidized by it.

Adult↗