Kay P. Maguire

Sexual Side-Effects of Contemporary Antidepressants: Review:

The aim of the present study was to review the sexual side-effects of contemporary antidepressants in Australia, comparing the selective serotonin re-uptake inhibitors (SSRIs) with venlafaxine, reboxetine, mirtazepine, duloxetine, bupropion, desvenlafaxine and agomelatine. Double-blind, randomized comparative studies of these antidepressants that included assessment of sexual dysfunction with validated rating scales in patients with major depressive disorder were identified from the literature using MEDLINE, EMBASE and PsychINFO databases. Bupropion and duloxetine caused significantly less sexual dysfunction than the SSRIs in short-term studies and reboxetine significantly less in both short- and longer term studies. Bupropion and agomelatine caused significantly less sexual dysfunction than venlafaxine. The evidence for mirtazepine having an advantage over the SSRIs is lacking and there are currently insufficient data for desvenlafaxine. Well-designed comparative studies of contemporary antidepressants with direct assessment of sexual side-effects as the primary outcome measure are scarce. Future studies should be randomized, double-blind, active controlled trials in sexually active subjects with major depressive disorder. There should be direct assessment of sexual function and depression using reliable, validated rating scales before and during treatment. Studies should assess treatment-emergent effects in patients with normal function and resolution of baseline dysfunction over treatment, in both the short and long term. Further research should compare available instruments for measuring sexual function, and include separate analyses of both remitters/non-remitters and male/female subjects.

The dexamethasone suppression test: Importance of dexamethasone concentrations

Plasma dexamethasone concentrations and cortisol response to dexamethasone were measured in 29 normal healthy volunteers, 23 depressed patients, and 10 patients with anorexia nervosa at 4:00 PM postdexamethasone. In each of the 3 groups, nonsuppressors had lower dexamethasone concentrations than suppressors. Of the subjects with plasma dexamethasone at or below 0.7 ng/ml, a significantly higher proportion (48%) were nonsuppressors compared to the proportion above 0.7 ng/ml (14%), all of whom were patients. Plasma dexamethasone concentrations in a subgroup of depressed nonsuppressors were high (mean 1.35 ng/ml), whereas the remainder were low (0.42 ng/ml) and were similar to the normal nonsuppressors (0.35 ng/ml), suggesting different mechanisms for nonsuppression in the subgroups. Plasma dexamethasone concentrations were similar in nonendogenous and endogenous depressives, in men and women, and in medicated and drug-free patients. None of the variables of age, weight, history of weight loss, Hamilton depression rating score, predexamethasone cortisol, or postdexamethasone cortisol were significantly correlated with plasma dexamethasone, except for body weight and a history of weight loss in the depressed group only. Mean plasma dexamethasone concentrations increased significantly from week 1 to week 2 in 7 depressed patients, whereas plasma cortisol decreased; however, the relationship between dexamethasone and cortisol varied considerably for individual patients.

The dexamethasone suppression test and plasma dexamethasone in generalized anxiety disorder

A Dexamethasone Suppression Test nonsuppression rate of 27% was found in a group of 30 generalized anxiety disorder patients before treatment. The dexamethasone concentrations in the eight nonsuppressors were significantly lower than in eight suppressors matched by sex and age, but were similar to those in five nonsuppressors from a matched normal control group. The dexamethasone concentrations in the generalized anxiety disorder suppressors and a matched group of eight normal control suppressors were similar. After successful nondrug behavioral treatment, all generalized anxiety disorder patients were suppressors. Posttreatment dexamethasone concentrations in the initial nonsuppressor patients remained significantly lower than in the initial suppressors. The results suggest that low plasma dexamethasone concentrations after 1 mg oral dexamethasone may confer a vulnerability to nonsuppression that may be expressed in the presence of high state anxiety.

Cigarette smoking and plasma nortriptyline levels

Cigarette smoking was found to have no effect on the steady‐state plasma levels of nortriptyline in a group of 22 smokers and 31 nonsmokers. Smokers achieved a mean steady‐state nortriptyline concentration oi 191.2 ± 141.3 ng/ml; nonsmokers had a level of 169.3 ± 92.4 ng/ml. Age, sex, and number of cigarettes smoked had no effect on the plasma concentrations achieved.

Sertraline in paired blood plasma and breast-milk samples from nursing mothers.

Paired blood and breast‐milk samples were collected from 10 nursing mothers receiving sertraline. Samples were collected at steady state when the patients had been taking stable doses of 50–150 mg/day over several weeks. Sertraline concentrations in both fluids were determined using a specific, validated HPLC method. Plasma and milk concentrations showed a wide inter‐individual variability for the same dose. Mean plasma concentrations were linearly related to dose, but this was not the case for breast‐milk concentrations. An overall milk to plasma ratio of 1·76±1·72 was recorded. The average dose to the infants ranged from 1·1 to 31·1 μg/kg, which is less than 2 per cent of the maternal dose per day. Further studies are necessary to determine if these doses are detrimental to the development of the infant. Copyright

Is diazepam an antidepressant

In double-blind sequential study, diazepam was compared with the proven antidepressant moclobemide, in patients with atypical depression. Both agents significantly improved depression ratings over eight weeks of treatment. Diazepam was a significantly better antidepressant than moclobemide at four week, although not at eight weeks. All patients ceased diazepam within one year and none reported withdrawal reactions. These data suggest the need to reconsider that benzodiazepines may be antidepressants and to study their possible antidepressant actions.

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 dexamethasone suppression test: A study in a normal population

One hundred healthy, non-depressed volunteers were given a standard dexamethasone suppression test (DST) to determine the appropriate criterion values of plasma cortisol to define suppression or nonsuppression. By radioimmunoassay (RIA) of cortisol, the criterion value for 5% nonsuppression was plasma cortisol greater than 187 nmol/l, and for suppression less than 153 nmol/l, with an indeterminate range between these values. Use of the widely accepted pre-determined criterion value of 138 nmol/l gave a significantly greater frequency of nonsuppression. Values of cortisol measured by two RIAs in a subset of 43 volunteers were not equivalent. With the experimentally determined criterion value, no significant differences between nonsuppressors and suppressors were found for any measured physical or psychological parameters. Women taking oral contraceptives had significantly higher plasma cortisol pre-dexamethasone and post-dexamethasone. Their exclusion did not alter the calculated criterion value for the remainder, but their separately estimated criterion value was significantly higher. Caution should be exercised when classifying the DST status of women on oral contraceptives, particularly when values are at the lower end of the nonsuppressor range. Determination of a separate normal range for them may be warranted.

Analysis of tricyclic antidepressant drugs in plasma and serum by chromatographic techniques

A review of methods for the determination of tricyclic antidepressants in plasma or serum, based on the application of chromatographic techniques, is presented. A general discussion of the techniques in terms of their precision, accuracy, sensitivity and selectivity, with respect to parent drug and metabolites, is used to facilitate a comparison of methods. No one technique can be claimed as the method of choice for these drugs, although gas-liquid chromatography with nitrogen selective detection has some strong claims, viz. generally good sensitivity and reproducibility of assays and ready availability of equipment in most laboratories. The ultimate choice of a method for determining tricyclics will be determined more by the clinical application (routine monitoring versus pharmacokinetics) than by other factors.

Pharmacokinetics of N-desmethyldiazepam after a single oral dose of clorazepate: The effect of smoking

SummaryThe pharmacokinetics of N-desmethyl-diazepam was evaluated after oral administration of clorazepate 20 mg to 12 healthy male volunteers (6 smokers; 6 non-smokers), aged 23–29 years. Plasma levels of desmethyldiazepam were measured by gas liquid chromatography. The half life of elimination (t1/2β) was significantly longer in the non-smoking volunteers than in the smokers: 54.7±17.7 versus 29.8±9.9 h (p<0.05). Peak plasma concentrations (Cmax) were higher in non-smokers than in smokers, 413±106 µg/l and 245±50 µg/l, respectively (p<0.05). The sedative effect of clorazepate was less severe in smokers than in non-smokers.