Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study.

The effects of an abrupt interruption of agomelatine, a new melatonergic/serotonergic antidepressant, were explored in a double-blind, placebo-controlled study. Paroxetine was used as active control. After 12 weeks of double-blind treatment with agomelatine 25 mg/day or paroxetine 20 mg/day, sustained remitted depressed patients were randomized for 2 weeks, under double-blind conditions, to placebo or to their initial antidepressant treatment. Discontinuation symptoms were assessed at the end of the first and second week of discontinuation with the Discontinuation Emergent Signs and Symptoms (DESS) checklist. One hundred and ninety-two sustained remitted patients were randomized to the 2-week discontinuation period. Patients who discontinued agomelatine did not experience more discontinuation symptoms than those who continued on agomelatine. Patients who discontinued paroxetine for placebo experienced significantly more DESS discontinuation symptoms, during the first week, compared to those who continued with paroxetine (respective mean number of emergent symptoms: 7.3+/-7.1 and 3.5+/-4.1, P<0.001). No significant difference was shown between the continuing and interrupting groups in the second week of discontinuation. By contrast to paroxetine, abrupt cessation of agomelatine is not associated with discontinuation symptoms.

Third-generation antidepressants: do they offer advantages over the SSRIs?

Third-generation antidepressants are a group of antidepressant agents of variable action, not confined to serotonin reuptake inhibition. These agents include venlafaxine, reboxetine, nefazodone and mirtazapine. Claims have been made for these agents in terms of improved efficacy, faster speed of onset of effect and greater safety in the treatment of depression compared with previous medications, such as the selective serotonin reuptake inhibitors (SSRIs). This article reviews the evidence for these improvements. Thirty active comparator studies were reviewed involving the third-generation antidepressant agents. While there were isolated reports of improvements over comparator agents for venlafaxine, reboxetine and mirtazepine, there were no convincing differences between third-generation agents and comparators in terms of overall efficacy, relapse prevention and speed of onset. The third-generation antidepressants were, however, of equivalent safety to SSRIs and maintained improvements in safety over first-generation agents.

The effect of single oral doses of zopiclone on nocturnal melatonin secretion in healthy male volunteers.

The effects of single oral doses of zopiclone and temazepam were investigated in eight healthy male volunteers using a single blind, placebo controlled cross over study. Doses of zopiclone were 7.5 and 15 mg while the dose of temazepam was 20 mg. Each dose was separated by at least a one-week washout period. For each subject the dim light melatonin onset (DLMO) was determined on a screening night and the drugs were administered at the time of the DLMO. Melatonin concentrations were determined by radioimmunoassay from plasma samples collected throughout the night. Both temazepam and zopiclone tended to reduce the amount of melatonin secreted, as determined by the area under the plasma concentration time curve. The differences from placebo were not statistically significant (F 3.31 = 1.07, P > 0.1). Similarly a repeated measures analysis of variance on the plasma concentration-time curves did not show any statistically significant differences between drugs and placebo (F 3.28 = 1.15, P > 0.1). There was no evidence from this study of a phase shifting effect of the drugs used. The reasons for the lack of effect on melatonin may be due to the differences in potency of the interaction of these drugs with the GABA-benzodiazepine-chloride ion channel.

Chiral determination of mirtazapine in human blood plasma by high-performance liquid chromatography.

A method is described for the determination of the two enantiomers of mirtazapine in human blood plasma by high-performance liquid chromatography. Measurements were performed on drug free plasma spiked with mirtazapine and used to prepare and validate standard curves. Levels of enantiomers of mirtazapine were also measured in patients being treated for depression with racemic mirtazapine. Mirtazapine was separated from plasma by solid-phase extraction using CERTIFY columns. Chromatographic separation was achieved using a Chiralpak AD column and pre-column and compounds were detected by their absorption at 290 nm. Imipramine was used as an internal standard. The assay was validated for each analyte in the concentration range 10-100 ng/ml. The coefficient of variance was 16% and 5.5% for(+)-mirtazapine for 10 and 100 ng/ml control specimens respectively and 15% and 7.3% for mirtazapine for 10 and 100 ng/ml control specimens respectively. This assay is appropriate for use in the clinical range. The range of plasma mirtazapine concentrations from eleven patients taking daily doses of 30-45 mg of racemate was <5 to 69 ng/ml for (+)-mirtazapine and 13-88 ng/ml for (-)-mirtazapine for blood specimens collected 10-17.5 h after taking the dose.

Quality of life and cognitive function of liver transplant patients: a prospective study.

The presence of cognitive impairment in end-stage liver disease is well recognized, as are patient reports of an impoverished quality of life. The aim of this study is to systematically evaluate the effect of orthotopic liver transplantation (OLT) on these factors. Thirty-two adult patients activated for OLT participated in the study. Assessments were made on activation and at 1, 3, and 9 months post-OLT, with 24 transplant recipients available for reassessment at 9 months. Two control groups (10 patients with nonalcoholic cirrhosis and 10 healthy volunteers) also completed the test protocol at four 2-month intervals. The test battery included the Austin Quality-of-Life Scale, Weschler Adult Intelligence Scale-Revised, Benton's Controlled Oral Word Test, and the Complex Figure of Rey. The OLT group showed significant improvement in cognitive performance and their reported quality of life. These changes were evident by 3 month post-OLT and remained stable at subsequent testing. The control groups typically remained stable over test occasions. Clearly, OLT extends life and, most importantly, improves patients' quality of life and their cognitive functioning.

The effect of gender on the melatonin suppression by light: a dose response relationship.

It is well known that light is an inhibitor of pineal melatonin secretion in humans. However, the effect of gender on the melatonin suppression by dim and bright light is still controversial. The present study investigated the effect of gender on the suppression of melatonin at five light intensities (0, 200, 500, 1,000, 3,000 lux). Five healthy men and women attended five testing sessions separated by one week. At each session, subjects were exposed to light from midnight to 0100 hours in a sitting position. Blood samples where collected at regular intervals and plasma melatonin concentration was measured using a specific radioimmunoassay. No gender differences were found in melatonin suppression by light at any of the five light intensities (p > 0.1). Furthermore, the mean melatonin suppression by light in both males and females was dose dependent (17% [200 lux], 40% [500 lux], 56% [1,000 lux] and 74% [3,000 lux]). Our findings suggest that melatonin suppression by light in intensity dependent, with no gender differences in light sensitivity.

Pindolol augmentation of antidepressants: a review and rationale.

OBJECTIVE: To critically review the literature on clinical trials in which pindolol, a 5HT1A receptor antagonist, has been used to augment the effects of antidepressants in patients with depression and to examine the pharmacodynamics and pharmacokinetics that may underlie such augmentations. METHOD: The available literature from the previous 10 years relating to the clinical use of pindolol in combination with antidepressants was critically examined. This was placed in the context of its pharmacodynamic rationale, and evidence supporting its use was critically reviewed. RESULTS: A number of open-label and placebo-controlled, double-blind trials on patients with depression showed conflicting results as to the value of adding pindolol to various antidepressant regimens in reducing latency or in augmenting the antidepressant effect in treatment-resistant cases. While pre-clinical studies using electrophysiological and microdialysis techniques suggest utility in terms of increases in extracellular concentration of 5-hydroxy-tryptamine (5HT) in serotonergic projection areas, few studies have examined the possibility of drug-drug interactions and subsequent elevated plasma levels of antidepressant. CONCLUSIONS: Pre-clinical studies suggest possible advantages of pindolol augmentation of antidepressant regimens and the achievement of faster acting antidepressants. The results of investigations in patients with depression have so far been conflicting. There exists the possibility of drug-drug interaction in pindolol/antidepressant augmentation strategies which remains to be examined.

Melatonin sensitivity to dim white light in affective disorders.

Both dim and bright light has been shown to suppress the nocturnal secretion of the pineal hormone melatonin. Early reports suggests that an abnormal response to light occurs in patients with bipolar affective disorder, where as patients with major depressive disorder respond similarly to controls. It has been suggested that this abnormal sensitivity of the melatonin response to light could be a trait marker of bipolar affective disorder. However reports lack consistency. Hence, we investigated the melatonin suppression by dim light (200 lux) in patients with bipolar affective disorder, seasonal affective disorder and major depressive disorder. Results suggest that a supersensitive melatonin suppression to light in bipolar affective disorder (p < .005), and seasonal affective disorder (p < .05), whereas patients with major depressive disorder display similar suppression to controls. The supersensitivity may be a mechanism where by phase-delayed rhythms, are resynchronised to a new circadian position. Conversely, an abnormality may exist in the pathway from the retina to the suprachiamatic nucleus.

The effect of age and pre-light melatonin concentration on the melatonin sensitivity to dim light.

The hormone melatonin is secreted at night from the pineal gland, with light being a potent inhibitor of its secretion. Age related decreases in plasma melatonin concentrations have indicated that this may be related to pineal calcification with aging. Recently, it was shown that the melatonin sensitivity to light may be a biological marker of bipolar disorder. However, on average, patients were older than the control group in most studies, and it is not known if age has an effect on the melatonin suppression by light. To test this hypothesis, the present study investigated the effect of age on the melatonin sensitivity to dim light (200 lux). Participants were grouped into three age groups. On the testing night, they were placed in a dark room from 21.00 h to 02.30 h. Light exposure was for an hour from midnight to 01.00 h. Blood samples were collected at regular intervals for measurement of plasma melatonin. No significant differences were found in the percentage suppression of melatonin within the age groups defined in the present study (P > 0.5). No correlation was also found between age and percentage suppression of melatonin (r2 = 0.007; P > 0.1). Our results suggest that the melatonin suppression by light (200 lux) is not affected by age.

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.

Reboxetine: a double-blind comparison with fluoxetine in major depressive disorder.

The aim of this study was to compare the efficacy and tolerability of reboxetine, a uniquely selective noradrenaline reuptake inhibitor, with the selective serotonin reuptake inhibitor, fluoxetine. A double-blind, randomized, parallel-group, multicentre design was employed. One hundred and sixty-eight patients with acute major depressive episodes were randomized to receive oral reboxetine (8-10 mg/day) or oral fluoxetine (20-40 mg/day). The treatment period was 8 weeks. Reboxetine and fluoxetine were similarly effective as assessed by the mean reduction in total Hamilton Depression Rating Scale score, the percentage of responders and patients in remission, Clinical Global Impression severity of illness and global improvement scores and Montgomery-Asberg Depression Rating Scale. A sub-analysis of patients with severe depression indicated that reboxetine had superior efficacy compared with fluoxetine. Both treatments resulted in some improvement in Social Adaptation Self-evaluation Scale total scores and this was more evident for those patients treated with reboxetine who achieved remission. Both treatments were well tolerated. The results indicate that reboxetine is an effective and well tolerated antidepressant, being more effective than fluoxetine in patients with severe depression, and more effective in terms of social functioning in those patients who achieved remission.

Effect of the menstrual cycle stage on the melatonin suppression by dim white light.

Patients with bipolar disorder have been shown to have a supersensitive melatonin suppression to dim white light (200 and 500 lux) compared to normal healthy subjects. Previous studies suggest menstrual cycle dependent changes in the melatonin rhythm, but it is not known if the melatonin sensitivity to light changes during the menstrual cycle. The present study investigated the melatonin suppression to dim white light (200 lux) in different stages of the menstrual cycle. No significant differences in the percent suppression of melatonin were found across the stages of the menstrual cycle (p = .97). Our findings suggest that the menstrual cycle hormonal changes do not affect the melatonin sensitivity to dim light in healthy controls.

Cade's observation of the antimanic effect of lithium and early Australian research.

John Cade had a major influence on the treatment of affective disorders following his report in 1949. His discovery of the efficacy of lithium as an antimanic agent was the result of an inevitable progression from the hypothesis of a metabolic basis for mania to clinical trials. Starting with animal studies, he progressed to patients. Further reports on lithium in the Medical Journal of Australia quickly followed in 1950 and 1951. The present paper reports on these and other Australian studies over the next few years. Lithium has moved in 50 years from a novel status to an internationally recognised major treatment of affective disorders.

Professional training in the practice of hypnosis--the Australian experience.

Increasingly around the world as clinicians and researchers alike become more sophisticated in their understanding of the hypnotic process, there is developing a conviction that the hypnotic state or process itself poses no inherent dangers for patients but that its inexpert use may. The solution to prevent potential patient harm is to ensure that all clinicians of whatever discipline have adequate and appropriate clinical training prior to being allowed to practice. Since 1985, in all the Australian states, the appropriate disciplines, already licensed to practice their profession, have completed 2 years part-time academic and clinical training in the nature and nuances of hypnosis (30 hours), practical experience of direct and indirect approaches, and supervised clinical case management (50 hours). At the end of the training they complete a 3 part examination of competence (clinical cases reports, written examination, and oral examination) in order to be accepted as members of the Australian Society of Hypnosis. Only by completing this training and peer reviewed assessment are clinicians able to receive the backing of the Society and recommendation to patients of their competence as clinicians using hypnosis. Recently in the states of Victoria and South Australia (and soon in the state of Queensland), the training program of the Australian Society of Hypnosis has been incorporated into a university diploma course, giving formal academic recognition to the approach to training. The University of Melbourne diploma course will be discussed with a view to illustrating these recent developments.

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.

Psychiatric illness in women: a review of the function of a specialist mother-baby unit.

OBJECTIVE: The aim of this paper is to describe a specialist program in a psychiatric mother-baby unit and to review the characteristics (including mothering skills) and outcomes on discharge of 36 women consecutively admitted to the unit over an intensive 6-month observation period. Changes in admissions to the same unit over 10 years were also compared. METHOD: Consecutive admissions were studied in terms of demographics, ethnicity, diagnosis, psychiatric history, psychiatric information and mother-infant data. RESULTS: The majority of women admitted suffered from schizophrenia or other psychotic disorders, with the second largest diagnostic criteria being depression. For 20 mothers, this was the first psychiatric admission and most admissions were voluntary. The mean length of stay was 21.7 days, representing a highly significant decrease in stay when compared to the past 10 years in the same unit. Mothering skills were found to be incompetent or only passable in 57% of women. A small improvement occurred by discharge, and the majority of women were not separated from their infants. CONCLUSIONS: The critical need to support these women and their infants in the long term was highlighted, with recommendations of outpatient and day programs, as well as supported accommodation.

Neurochemical effects of the enantiomers of mirtazapine in normal rats.

The present study was designed to examine the neurochemical effects of (+/-)-mirtazapine (10 mg kg(-1) i.p.) and its enantiomers in rats. Male Sprague-Dawley rats received either (+)-mirtazapine, (-)-mirtazapine, (+/-)-mirtazapine or vehicle, by intraperitoneal injection for two weeks. Maximum change in temperature from baseline, following a single dose of the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.15 mg kg(-1) s.c.), was used to assess the function of the 5-HT1A receptors. Chronic drug treatment potentiated this response, with (+/-)-mirtazapine > (-)-mirtazapine > (+)-mirtazapine. Receptor changes were also observed with a slight decrease in beta1-adrenoceptor density, although this failed to reach significance. A significant decrease in beta1-adrenoceptor affinity was observed following (-)-mirtazapine treatment. All drugs tested significantly reduced the density of the 5-HT2 receptors. Results of the present study suggest that in so far as alterations in these receptor populations are important for the therapeutic action of antidepressants, neither of the enantiomers appear to be more active than the racemic mixture.