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: 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.

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.

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: 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.

Post-stroke depression.

Depression is present in 25-30% of stroke patients: though associated with physical disability and loss of function, it cannot be explained simply as a response to the disability. The severity of depression correlates with proximity of the lesion to the left anterior frontal pole, while right hemisphere lesions show the reverse trend. Post-stroke depressions may last more than 7-8 months without treatment, and are highly correlated with a failure to resume premorbid social and physical activities. However, this is a group of patients whose recovery could be hastened by appropriate antidepressant treatment, though most antidepressants are of limited value in the treatment of these patients, because of side-effects or possible toxicity. Since moclobemide has few side-effects it may be uniquely well tolerated in this group of patients, having proven efficacy for both endogenous and reactive depressions.

Clinical overview on moclobemide.

1. Moclobemide is a novel benzamide reversible inhibitor of monoamine oxidase A and has clinical efficacy in a wide spectrum of depressive illness including endogenous and non-endogenous depression, in younger adults and in the elderly. 2. Comparisons have shown similar efficacy to all main classes of antidepressants and much greater tolerability and safety in overdose than tricyclic antidepressants. Clinically, it is neither sedative nor alerting. 3. There is no need for dietary restrictions for patients on moclobemide on a normal diet, and drug interactions are few and usually mild. Specific cautions are noted with pethidine and with selective serotonin re-uptake inhibitor antidepressants. 4. Moclobemide is a useful addition to the range of antidepressants in clinical practice.

Comparison of moclobemide with selective serotonin reuptake inhibitors (SSRIs) on sexual function in depressed adults. The Australian and German Study Groups.

OBJECTIVE: To compare the emergent sexual effects of moclobemide and selective serotonin reuptake inhibitors (SSRIs) during acute and maintenance therapy in routine practice. METHOD: 268 patients were evaluated for sexual function at baseline, 6 weeks, 3 and 6 months of treatment using physician ratings and self-rating questionnaires. Patients received moclobemide, an reversible monoamine oxidase A inhibitor (RIMA), or a SSRI (fluoxetine, fluvoxamine, paroxetine, sertraline). RESULTS: Baseline values were similar in all groups. Incidences of impairments of sexual functioning with treatment, whether clinically relevant or not, were 24.3% with moclobemide and 61.5% with SSRIs (physician ratings), with no significant tolerance to these effects. There was a suggestion of differences between the SSRIs in their specific dysfunctions they cause. SSRIs (21.6% of patients) had about ten times the moclobemide rate (1.9%) of sexual dysfunction reported as adverse events. Antidepressant efficacy was comparable between treatments. CONCLUSION: In patients for whom sexual function is important or sexual dysfunction is present, moclobemide should be considered a first line antidepressant.

Reactions of first-year medical students to their initial encounter with a cadaver in the dissecting room.

This study reports the results of a 1986 questionnaire survey of 100 first-year medical students regarding their preparation for and reactions to their first encounter with a human cadaver in the dissecting room. The students were aware of psychological and physical reactions to this experience, and although they felt adequately prepared prior to the class, expressed a desire for greater preparation afterwards, particularly through more discussion of the experience with the anatomy staff. A surprising number of the students (62) had had prior exposure to a dead human body, which was a significant influence upon their reactions. The results of this study suggest a need for improving both the preparation for coping with dissection and the follow-up opportunities for dealing with professional and emotional issues raised during human dissection.

The psychomotor effects of single and repeated doses of hypnotic benzodiazepines.

Benzodiazepine hypnotics are used for short periods in low doses in healthy people when stressed and in patients with insomnia. This study examined psychomotor impairment in healthy young males and females after 1 and 7 nights of flunitrazepam (1 mg), nitrazepam (2.5 mg) and temazepam (10 mg). There were substantial inter-individual variations. Results showed that no drug significantly affected psychomotor performance at these doses after single or repeated administration. The number and severity of side-effects were significantly greater after the first night with temazepam and 7 nights with nitrazepam, although this may reflect a statistical artefact rather than a significant clinical finding. The difficulties in performing adequately controlled psychopharmacological studies at low doses are highlighted. Given the large intra- and inter-subject variances, small drug effects would necessitate large sample sizes (21 to 600 subjects at the 95% level of chance of detection) depending on the variable. The study suggests there is minimal impairment with low dose hypnotic drugs and a need to individualize treatment.

Moclobemide for anxiety disorders: a focus on moclobemide for panic disorder.

Moclobemide is a reversible selective inhibitor of monoamine oxidase A. It has proven efficacy in a wide range of depressive disorders, including agitated anxious depression. In an international, multicentre, double-blind parallel-group study, the tolerability and efficacy of moclobemide were compared with that of the selective serotonin reuptake inhibitor fluoxetine. The target dose of moclobemide was 450 mg/day in the dose range of 300-600 mg/day, while the target dose for fluoxetine was 20 mg/day in the dose range of 10-30 mg/day. There were two consecutive studies. The first was an 8-week short-term study of acute adverse events, tolerability and efficacy. The efficacy data showed no significant difference between moclobemide and fluoxetine. Evaluation of the tolerability in a long-term study of up to 1 year is still in progress. A review of the moclobemide safety database for panic disorder with 624 patients showed a marginal increase in events with moclobemide compared with placebo for insomnia (11.2%), dizziness (4.5%) and dry mouth (3.7%), with rates for headaches and nausea lower for moclobemide than placebo. These data suggest moclobemide is a well tolerated and effective treatment for panic disorder.

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 classification of anxiety disorders.

A brief outline of some of the diagnostic systems for classifying the anxiety disorders are presented. This includes historical diagnoses, as well as systems of the recent past and those in current use. Some of the research issues and results leading to these diagnostic systems have been considered, as well as the way that a diagnostic system could have adverse effects in limiting research and the understanding of the anxiety disorders and their interplay, one with another. Finally a revised diagnostic system for the anxiety disorders is introduced, which, it is suggested, will overcome some of the serious criticisms of the current diagnostic systems.

The new and newer antianxiety agents.

Anxiolytic drugs are adjuncts to non-pharmacological treatments for anxiety. Alcohol and tobacco remain the major psychoactive agents that are used in our community. Benzodiazepine drugs are the agents of choice if an acute reduction in anxiety or intermittent therapy is needed and are helpful for long-term use in a few patients. For panic disorders, alprazolam is effective for short- and long-term treatment, although it needs a slow reduction in dosage and carries a risk of withdrawal reactions in about 30% of sufferers. Clonazepam also may help panic attacks and possibly other benzodiazepine agents would show similar effects at equivalent doses. Antidepressant drugs, including monoamine-oxidase inhibitor agents, although more toxic and sometimes less tolerated than is alprazolam, have antipanic effects in high doses and are of use for prolonged therapy for panic disorders. Neuroleptic agents' general usefulness as anxiolytic drugs is restricted because of their acute and long-term toxicity. There is no place for the use of antidepressant or neuroleptic drugs as treatments of first choice in uncomplicated generalized anxiety. beta-blocking agents have limited adjunctive use for performance anxiety and social phobias. Buspirone heralds a new class of anxiolytic agents. Buspirone has advantages in patients who can tolerate its slow onset of action, with reduced psychomotor effects, lower interactive effects with cortical depressant substances and a seeming lack of dependency or any withdrawal syndrome.

Antidepressants, alcohol and psychomotor performance.

The acute psychomotor effects of moclobemide, a reversible inhibitor of MAO-A antidepressant (100 and 300 mg) compared with amitriptyline (25 and 75 mg) showed that moclobemide caused no significant impairment in contrast with amitriptyline, which caused significant impairment at both doses. Two other studies are reviewed. One study reported the acute effects of moclobemide (100 and 300 mg), trazodone (100 mg), placebo, and alcohol (0.5 g/kg) or placebo in an elderly group: moclobemide caused little impairment or alcohol potentiation and may reverse some alcohol impairment, whereas trazodone caused substantial impairment and alcohol potentiation. Another study of the acute and chronic effects of moclobemide (200 mg 3 times daily) or clomipramine (25 mg twice daily) and their interactions with alcohol (blood alcohol concentration 0.6 g/l) showed that alcohol caused significant impairment, whereas clomipramine tended to enhance and moclobemide to reduce some impairment. Moclobemide appears to be an antidepressant with few psychomotor effects and minimal alcohol potentiation and may reduce some alcohol impairment.