Determination of nefazodone and its pharmacologically active metabolites in human blood plasma and breast milk by high-performance liquid chromatography.

A method is described for the determination of nefazodone and its active metabolites hydroxynefazodone, the dione BMS-180492 and m-chlorophenylpiperazine in blood plasma and expressed human milk based on reversed-phase high-performance liquid chromatography. Measurements were performed on drug-free plasma and expressed human milk spiked with nefazodone and metabolites to prepare and validate standard curves and specimens collected from nursing mothers. Parent drug and metabolites were separated from the biological matrices by solid-phase extraction using CERTIFY columns. Chromatographic separation was achieved with a C18 column and compounds were detected by their absorbance at 205 nm. Trazodone was used as an internal standard. The assay was validated for each analyte in the concentration range 200 to 1200 ng/ml.

Antidepressant efficacy and tolerability of the selective norepinephrine reuptake inhibitor reboxetine: a review.

Reboxetine is a unique selective norepinephrine reuptake inhibitor (NRI) with proven antidepressant efficacy in pharmacologic and biochemical tests predictive of antidepressant properties. Comprehensive clinical trials, including 8 placebo-controlled and/or active treatment-controlled studies, plus 4 open studies, have assessed the short-term and long-term efficacy and tolerability of reboxetine in patients with major depressive disorders and dysthymia. Results from a total of 690 patients who entered 5 open or placebo-controlled studies are summarized in this paper. Four hundred forty-nine patients with a diagnosis of either major depressive disorder or dysthymia were treated with reboxetine in these clinical studies of 4 weeks' to 12 months' duration. In a 6-week placebo-controlled study, clinically significant improvement (> or = 50% reduction in Hamilton Rating Scale for Depression total score) was observed at last assessment in 74% of reboxetine-treated patients compared with 20% of patients in the placebo group. Similar results were observed in the 6-week run-in phases of the 3 long-term studies, where the efficacy of reboxetine was maintained over the 12-month study period. Reboxetine was well tolerated; adverse events reported were mainly mild to moderate in severity, and there were no clinically significant changes in vital signs or laboratory parameters. The first in its class, reboxetine, a selective NRI, will provide a valuable addition to the existing armamentarium of agents used in the treatment of depression.

The effect of atenolol, a beta1-adrenergic antagonist, on nocturnal plasma melatonin secretion: evidence for a dose-response relationship in humans.

Pineal beta1-adrenergic receptors are involved in the regulation of melatonin secretion. The involvement of beta1-adrenergic receptors has been demonstrated by the ability of acute administration of beta-antagonists to suppress the nocturnal rise of circulating melatonin and its urinary metabolite 6-sulphatoxymelatonin (aMT6s). The present study was undertaken to examine the relationship between increasing doses of atenolol and nocturnal plasma melatonin concentrations. Six healthy subjects participated in the study for a period of 5 weeks. Subjects were administered placebo, 12.5, 25, 37.5, and 50 mg doses of atenolol in a randomized single blind design. Each dose was separated by a 1 week washout period. Blood samples were collected at regular intervals from 19.00 hr to 06.00 hr. Repeated measures analysis of variance showed a dose-dependent decrease in plasma melatonin concentrations (P<0.01). A Student Newman-Keuls post hoc test indicated significant differences between placebo and all doses of atenolol (P<0.05). The results demonstrate a dose-dependent relationship between beta1-receptor blockade and suppression of nocturnal plasma melatonin in humans.

Platelet [3H]paroxetine binding in panic disorder.

Platelet [3H]paroxetine binding was measured in 20 patients (14 females, six males) with panic disorder and 20 normal controls (14 females, six males). For patients with panic disorder, Bmax was 1987 +/- 1135 fmol/mg protein (mean +/- SD) compared with control Bmax values of 1626 +/- 611 fmol/mg protein. The mean Kd value for the patients was 0.076 +/- 0.056 nM and for the controls was 0.083 +/- 0.033 nM. ANCOVA indicated no significant effect of sex, diagnosis (panic disorder vs. normal controls) or season of sampling on either Kd or Bmax. The data provide no evidence for an abnormality of the platelet uptake mechanism in panic disorder.

Plasma cortisol and 11-deoxycortisol activity in depressed patients and normal volunteers.

Plasma cortisol and 11-deoxycortisol were measured in 30 depressed patients and 110 normal volunteers before and after a 1.0 mg dexamethasone suppression test (DST). Post-dexamethasone plasma cortisol, 11-deoxycortisol and the cortisol/11-deoxycortisol ratio were significantly higher in the depressives compared to the controls, even when age and sex were taken into account. Pre-dexamethasone plasma cortisol, post-dexamethasone cortisol, 11-deoxycortisol and their ratio were significantly higher in the cortisol nonsuppressors than in the suppressors. The measurement of post-dexamethasone 11-deoxycortisol and the ratio did not differentiate between endogenous and reactive depression. Using the normative data, we explored several methods for determining a criterion value to define abnormal post-dexamethasone plasma 11-deoxycortisol and the cortisol/11-deoxycortisol ratio in depressed patients. All showed poor sensitivity and a low positive predictive value for depression. The measurement of 11-deoxycortisol thus does not enhance the clinical utility of the DST.

The dexamethasone suppression test in anorexia nervosa. The influence of weight, depression, adrenocorticotrophic hormone and dexamethasone.

When 20 female anorexic in-patients were investigated with weekly DSTs, 10 had an abnormal result at initial testing. There was no identifiable relationship between severity of weight loss and DST status; % ideal body weight was no different between suppressors and non-suppressors. There was no consistent relationship between normalisation of the DST response and weight gain. Depressive symptoms were common, with half the patients scoring 20 or more on the HRSD. Plasma ACTH concentrations before and after the DST were normal. There was a significant negative correlation between plasma dexamethasone concentrations and pre- and post-dexamethasone plasma cortisol concentrations.

Dexamethasone kinetics in depressed patients before and after clinical response.

Dexamethasone pharmacokinetics were measured in 19 depressed patients, 10 dexamethasone suppression test (DST) nonsuppressors and nine suppressors, following a 1 mg oral dose in tablet form at 2300 h. Median dexamethasone concentrations were significantly lower in the nonsuppressors from 3-16 hr post-administration. Nonsuppressors had a significantly lower area under the curve than suppressors, and plasma clearance was significantly faster in the nonsuppressors than in the suppressors. Eleven patients, six nonsuppressors and five suppressors, agreed to a repeat DST after clinical improvement when all six nonsuppressors had normal DST responses. There were no significant differences between the median dexamethasone concentrations, or any of the pharmacokinetic parameters measured, of the "normalising" nonsuppressors and the suppressors. Dexamethasone kinetics were altered in depressed nonsuppressors but became normal with remission of depressive symptoms and normalisation of the DST response.

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.

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.

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.

Prediction of outcome in depressed patients by weekly monitoring with the dexamethasone suppression test.

Forty-three depressed patients in hospital were studied with weekly dexamethasone suppression tests (DSTs) and were followed as out-patients for at least three months after discharge. The detection rate of patients with LHPA axis dysfunction increased from 41% with a single DST to 59% with serial DSTs. There was a poor correlation between weekly post-dexamethasone cortisol levels and Hamilton depression rating scores. In patients with evidence of LHPA axis dysfunction, a DST at discharge discriminated effectively between a good and a poor outcome group; persistent non-suppression was strongly linked with a relapse of depression in the first three months after discharge. In general, our results support previous claims that the DST is a state marker for depressive illness.

Tyramine pressor response with moclobemide--a reversible monoamine oxidase inhibitor.

Moclobemide is a reversible, short-acting monoamine oxidase inhibitor (MAO1), specific for MAO A. To study moclobemide effects on the tyramine pressor response, we gave 12 depressed patients (2 males, 10 females; mean age 47, SD 11 years) an i.v. tyramine test after 7 days drug free. The mean (+/- SD) tyramine dose to raise systolic blood pressure 30 mmHg was 5.6 +/- 2.5 mg. Repeat tyramine testing after 2 weeks of treatment with moclobemide (280 +/- 90 mg/d) showed the tyramine dose required was reduced to 2.5 +/- 1.6 mg (n = 8). The mean (+/- SD) increase in sensitivity to tyramine was 2.9 +/- 1.8. Four patients did not have repeated tyramine tests as testing was discontinued because of tyramine-induced cardiac arrhythmias. Moclobemide seems an effective antidepressant with less tyramine sensitivity than MAOIs in current use.

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 effects of weight change on the dexamethasone suppression test in depressed and anorexic patients.

Prior studies on weight change and hypothalamic-pituitary-adrenal (HPA) axis functioning are reviewed. Data on 58 depressed and eight anorexic patients is presented. No significant difference in the frequency of cortisol non-suppression in the dexamethasone suppression test (DST) was found between depressed patients with a history of weight loss and those without, nor between depressed patients who lost weight during their first week in hospital and those who did not. Mean weight loss of suppressors did not significantly differ from that of non-suppressors. Of 12 patients whose DST normalised during their stay in hospital, only four gained weight. Five anorexics who were non-suppressors were less than 70% of their ideal body weight (IBW), while three suppressor anorexics were greater than or equal to 70% IBW. These results indicate that mild to moderate weight change is not a significant influence on DST response in depression.

The sexual side-effects of antidepressant medication: a double-blind comparison of two antidepressants in a non-psychiatric population.

Clinical reports have suggested that antidepressant medication may contribute to the sexual dysfunction experienced by some depressed patients. A double-blind trial in a non-psychiatric male population compared amitriptyline (tricyclic), mianserin (tetracyclic) and placebo for their effects on nocturnal sexual arousal. In a three-way crossover design active drug or placebo were taken for two weeks preceding measurement of the frequency, amplitude and duration of nocturnal penile tumescence and synchronous sleep indices. Both active compounds significantly decreased the amplitude and the total duration of nocturnal erections. The effects on sleep indices were as previously reported. Few differences were found between the tricyclic and tetracyclic drugs. Some implications of these findings are considered.

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.

Maprotiline in affective illness. Plasma concentration and clinical response.

Twenty patients suffering from endogenous depression were treated with maprotiline for 4 weeks. Blood samples were collected at weekly intervals and severity of depression assessed using the Hamilton Depression Rating Scale. No simple relationship between plasma maprotiline concentration and amelioration score was observed at week 3 (rs = 0.25) or week 4 (rs = -0.05). No significant difference in plasma concentrations between responders and non-responders was observed at week 4. Maprotiline was effective as an antidepressant in some patients.

Clinical pharmacokinetics of dothiepin. Single-dose kinetics in patients and prediction of steady-state concentrations.

The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. 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 micrograms/L at 3 +/- 1.2h. Mean (+/-SD) estimates of other parameters were as follows: absorption half-life 1.1 +/- 1.1h; distribution half-life 2.2 +/- 0.8 h; 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 micrograms/L at 3.5 +/- 1.3h with an elimination half-life of 22 +/- 12 h. The mean peak plasma concentration of northiaden was 6 +/- 3 micrograms/L at 4.5 +/- 1.1h, with an elimination half-life of 31 +/- 12 h. 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 150 mg nocte.