Burrows Gd

Progesterone and the premenstrual syndrome: a double blind crossover trial

A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Mooss menstrual distress questionnaire, Beck et als depression inventory, Spielberger et als state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.

PLASMA CONCENTRATION OF NORTRIPTYLINE AND CLINICAL RESPONSE IN DEPRESSIVE ILLNESS

Abstract The relation between plasma-nortripty-line levels and clinical response has been examined in thirty-two patients with depressive illness on an oral dose of 150 mg. nortriptyline daily. There was no significant correlation between the plasma level and clinical response at 4 or 6 weeks. The patients with a significant clinical response at 4 weeks (59%) and at 6 weeks (79%) had similar plasma-nortriptyline levels to those patients who did not respond. The results show that on a fixed oral dose of 150 mg. per day, it is not possible to predict the clinical response from the plasma-nortriptyline level. However, the clinical response seen in most patients on this dose indicates that it is a suitable daily dose for the initial treatment of depressive illness.

Definition and differential diagnosis of treatment-resistant depression

There are no agreed criteria for treatment-resistant depression, but the failure to respond adequately to two successive courses of monotherapy with pharmacologically different antidepressants, given in an adequate dose for sufficient time is one pragmatic definition. Inherent within this definition are notions of what constitutes an adequate dose of drug, the length of treatment and pharmacological specificity of treatments. When these factors are accounted for, treatment resistance may be encountered in 15–20% of patients. In attempting to treat such patients a number of pharmacological strategies have been adopted and some are briefly reviewed. Psychosurgery may have a role to play in cases of absolute treatment resistance.

Tricyclic antidepressant drugs and cardiac conduction

Abstract 1. 1. Distal intracardiac conduction defects were observed inpatients ingesting both toxic and therapeutic doses of tricyclic antidepressants (TCA). 2. 2. In a crossover comparative study of doxepin-nortriptyline (150 mg/day for 3 weeks) six out of seventeen patients on nortriptyline and only one patient on doxepin showed significant prolongation of the QRS interval. 3. 3. Plasma levels of doxepin (52 ± 6 ng/ml) were lower than those of nortriptyline (196 ± 29 ng/ml). 4. 4. An in vitro study of TCA has shown that the isolated perfused guinea pig heart could provide a toxicological model for studying the arrhythmogenic effects of TCA in man.

The effect of dim light on suppression of nocturnal melatonin in healthy women and men

SummaryThe present study investigated the effect of dim white light on nocturnal plasma melatonin in males and females. Subjects were exposed to light between 2400hr and 0100hr. No significant gender differences were found with both 200lux (p > 0.1) and 500lux (p > 0.1) of light. Furthermore the amplitude of the melatonin rhythm was not significantly different with gender. This suggests that at low intensities the melatonin sensitivity to light is not differentially regulated between sexes.

An evaluation of maprotiline intravenous kinetics and comparison of two oral doses

SummaryThe kinetics of maprotiline have been evaluated in six normal volunteers following rapid intravenous administration of 75 mg. Blood levels could be resolved using a biexponential equation. Mean estimates of half-life, volume of distribution and systemic clearance were 40±15 h, 51.7± 18.01 l/kg and 0.92±0.24 l/kg/h, respectively. Blood/plasma concentrations varied between subjects from 0.77 to 1.64. A comparison of the bioavailability of two oral doses (a 75 mg tablet and three 25 mg tablets) was carried out in the same volunteers. No significant difference was observed between the maprotiline concentrations obtained for the two doses at sampling times up to 26 h. No significant difference was found in the area under the concentration vs. time curves for the two doses. Equivalent bioavailability can be assumed. On the basis of the intravenous injection study, systemic bioavailability averaged 66% and 70% for the 75 mg and three 25 mg tablets respectively.

Clinical Pharmacokinetics of Dothiepin

SummaryThe pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (±SD) peak plasma concentrations of dothiepin were 49 ±27 μg/L at 3 ± l.2h. Mean (± SD) estimates of other parameters were as follows: absorption half-life 1.1 ± 1.1h; distribution half-life 2.2 ± 0.8h; elimination half-life 25 ± 7h; apparent volume of distribution 70 ± 62 L/kg; and oral clearance 2.1 ± 1.6 L/kg/h.The mean (±SD) peak plasma concentration of dothiepin S-oxide was 125 ± 43 μg/L at 3.5 ± 1.3h with an elimination half-life of 22 ± 12h. The mean peak plasma concentration of northiaden was 6 ± 3 μg/L at 4.5 ± 1.1h, with an elimination half-life of 31 ±12h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers.When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin.The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks’ treatment with dothiepin 150mg nocte.

A pharmacokinetic study of mianserin

SummaryThe kinetics of mianserin have been evaluated in eight healthy male volunteers following a single oral dose of 60 mg. Plasma and blood concentrations of mianserin were measured by gas chromatography-mass fragmentography. The peak blood concentration observed was 65 µg/l at 3 h following the dose. Mean kinetic parameters (and range) calculated from the blood concentrations were: (t1/2)abs 1.1 h (0.3–2.8), (t1/2)α 2.5 h (0.9–4.7), (t1/2)β 21 h (14–33), (Vd)β 27.5 l/kg (16.8–46.5) and Cloral 0.98 l/kg/h (0.47–1.75). Blood/plasma concentration ratios ranged from 0.50–0.74.

Assessment of the antidepressant activity of dothiepin and its metabolites by preclinical tests

The affinities of dothiepin and its principal metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide for [3H]imipramine binding sites in the rat cortical homogenates, and for [3H]spiperone and [3H]serotonin receptor sites in preparations from the rat frontal cortex and hippocampus were studied. As inhibitors of [3H]imipramine binding, the strengths of the drugs are, in terms of their IC50 (concentration corresponding to 50% inhibition): dothiepin 2.8 X 10(-6) M, northiaden 5.0 X 10(-6) M, northiaden sulphoxide 4.0 X 10(-5) M and dothiepin sulphoxide 3.2 X 10(-5) M. The potencies of the drugs in inhibiting serotonergic binding followed a similar trend. Using frontal cortical tissue suspensions and [3H]spiperone, the IC50 values were determined to be: dothiepin 4.2 X 10(-6) M, northiaden 5.0 X 10(-6) M, northiaden sulphoxide 1.6 X 10(-4) M and dothiepin sulphoxide 1.6 X 10(-4) M; whereas in hippocampal suspensions and using [3H]serotonin, the IC50 values were 2.5 X 10(-6) M, northiaden 4.0 X 10(-5) M, dothiepin sulphoxide 2.5 X 10(-4) M and northiaden sulphoxide greater than 10(-3) M. The influence of the drugs on the uptake of [14C]serotonin into human platelets was also investigated. All had an inhibitory effect upon the uptake, the order of potency being dothiepin greater than northiaden greater than northiaden sulphoxide greater than dothiepin sulphoxide. Plots of 1/v versus 1/s showed that the inhibition was competitive for all four compounds.

Renal Function Related Changes in Lithium Kinetics

The renal clearance of lithium will decrease, and hence the risk of acute lithium toxicity will increase, in any situation leading to dehydration and sodium depletion. Patients on long term lithium therapy with progressively declining urinary concentrating ability may be at special risk in this regard.Chronic histological changes in the kidney attributed to lithium therapy correlate with age rather than with the duration of lithium therapy. Age-related renal histological changes are associated with decreased glomerular filtration rate and therefore reduced renal lithium clearance. Thus, the dose of lithium should be reduced with advancing age.