[Psychiatry]. / Psychiatrie.

Introduced this year on the Swiss market, duloxetine (Cymbalta) is a new antidepressant which inhibits the reuptake of noradrenaline and serotonin. Clinical studies have shown its efficacy in depression as well as in neuropathic pains (60-120 mg/day) with a good tolerability. In this paper are also included short reviews about the two large American studies developed by the National Institute of Mental Health in the fields of the treatment for depression (STAR-D) and of the antipsychotic treatments for schizophrenia (CATIE study). Its also reviews two questions of present interest: the use of the second generation antipsychotics for the treatment of bipolar depression and the concept of bipolar disorders in children.

Comparative efficacy of antidepressants on anxiety features in depression: A meta-analysis of double-blind studies of imipramine and moclobemide against placebo.

INTRODUCTION: We carried out a meta-analysis of data for 950 depressed patients from all double-blind, placebo-controlled comparative studies of moclobemide against imipramine. The aim of the analysis was to determine: 1 if the two antidepressants reduce anxiety symptoms as effectively as symptoms of depression; 2. if there are differences in the anti-anxiety effects; and 3. if the severity of anxiety symptoms influences the outcome of treatment. METHOD: The analysis was done in sub-groups of patients classified according to different definitions of anxiety and to the degree (mild, moderate, severe) of psychic and somatic anxiety present at baseline. The definitions and the criteria for the severity of anxiety were derived from the HAMD-17 anxiety item scores (items 10 and 11) and HAMD-17 anxiety sub-scales (ANXP and SOMA). The application of various definitions of anxiety (single-item and composite sub-scale scores) served to check the consistency, reproducibility and generalizability of the results. The criteria of efficacy and of the outcome of treatment, which were set in advance, were either: 50% reduction of the HAMD anxiety sub-scale; or percentage of global improvement (CGEA, very much and much) at the end of treatment (4 weeks). RESULTS: The results showed that moclobemide and imipramine are equally effective in reducing psychic and somatic anxiety in depressed patients, independent of the severity of anxiety or how it was defined. The criterion of 50% decrease of anxiety scores (at week 4) was consistently reached by 60-70% of patients in all drug sub-groups. The time course of effects on anxiety symptoms was similar with both drugs. It ran parallel to the regression of depression, with significant improvement of anxiety symptoms by week 2 on all measures. The frequency of benzodiazepine (BDZ) co-administration was not systematically correlated with the severity of anxiety. Moreover, co-prescription of BDZ did not change the outcome of drug treatment, with respect either to anxiety symptoms or global therapeutic efficacy. In placebo groups, significant negative interactions were found between severity of anxiety and the efficacy of treatment, which decreased with increased anxiety. The incidence of adverse events with moclobemide was barely higher than in the placebo group. Insomnia (4.9%) was the only adverse event significantly higher with moclobemide than with other treatments. Drop-out rates in drug groups were similar (27%) and unrelated to the severity of anxiety. In the placebo group, drop-outs were significantly higher than in drug groups (39%), and were positively correlated with the severity of anxiety. CONCLUSION: The results of this study indicate that anxiety symptoms in depressed patients respond similarly to moclobemide or imipramine and that the severity of these symptoms (or the co-prescription of benzodiazepine) has no influence on either the magnitude of anti-anxiety effects or on overall outcome. (Int J Psych Clin Pract 2000; 4:111-117).

Milnacipran: an antidepressant with dual selectivity of action on noradrenaline and serotonin uptake.

Milnacipran is a new antidepressant which possesses potent and doubly selective action in that it inhibits both the re-uptake of serotonin and noradrenaline without any effect on other neurotransmitter systems. The almost equipotent inhibition of serotonin and noradrenaline by milnacipran is functionally reflected in the several-fold and long-lasting increase of the levels of these monoamines in the brain and in antidepressant-like effects in animals. In man, milnacipran distinguishes itself from many other antidepressants by its simple pharmacokinetics. It shows linear dose-concentration relationship over a dose range of 25-200 mg/day. It is rapidly and extensively absorbed and almost completely eliminated after 12 h (t1/2 approx. 8 h). Steady-state plasma levels are reached within 32-48 h after twice daily oral administration. Milnacipran is highly bioavailable (>85 per cent) and its metabolism does not involve the cytochrome P450 enzyme system. In clinical studies, milnacipran showed antidepressant efficacy similar to that of TCAs and SSRIs and superior to that of placebo. At the optimum dose of 100 mg/day, after 4-8 weeks of treatment, 60-64 per cent of in- or out-patients with major depression improve (>/=50 per cent reduction of HAMD and MADRS score) and about 32-39 per cent of them achieve full remission (HAMD score

Fluoxetine versus moclobemide: cross-comparison between the time courses of improvement.

Competitive statistical methods were used in a meta-analysis of the data of 440 fluoxetine-treated and 437 moclobemide-treated patients in order to address the issue of the timing of recovery from depression, and to elucidate potential differences in the onset of action between the two different classes of antidepressants. In spite of large biochemical and pharmacological differences, fluoxetine and moclobemide turned out to be virtually identical with regard to the overall efficacy, proportions and time characteristics of premature withdrawal, and most notably, the time course of recovery. The onset of improvement occurred in the majority of cases within the first two weeks of treatment and was highly predictive for the outcome after six weeks. The analyses yielded no indication of a delayed onset of action of antidepressants. Given the apparent nonspecificity of antidepressants, together with their relatively modest response rates, future research will need consider whether mechanisms different from those related to the monoaminergic systems may be involved in the pathogenesis of depression.

Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies.

Blood pressure decrease, associated with postural hypotension, as well as spontaneous hypertension are considered to be typical side-effects of conventional, irreversible and nonselective MAO (A+B) inhibitors. The new generation of reversible MAO-A inhibitors is, however, expected to have negligible cardiovascular effects and low propensity to induce either blood pressure increases or decreases. But, the true incidence of such changes is largely unknown since observation studies, specifically assessing the frequency of blood pressure changes, in unselected population of patients treated in the practice, are lacking.

Assessment of sexual dysfunction in depressed patients and reporting attitudes in routine daily practice: Results of the postmarketing observational studies with moclobemide, a reversible MAO-A inhibitor.

OBJECT: The aim of this study was to assess the effect of moclobemide on sexual dysfunction in depressed patients treated under routine conditions in private practice and hospital settings. METHOD: sexual function was systematically assessed by a specific questionnaire and by recording spontaneously reported adverse events during large prospective postmarketing surveillance studies with moclobemide, carried out in Germany between 1992 and 1995. The data of 4333 patients were collected in two different settings: (a) specialized psychiatric and neurological private practices and (b) psychiatric hospitals. RESULTS: Up to 70% of depressed patients suffered from Some type of sexual dysfunction at baseline and in about two thirds the dysfunction was rated as moderate to severe. The severity and frequency of sexual dysfunction corresponded well to the severity of depressive syndrome. Sexual functions improved during treatment with moclobemide and the extent of improvement corresponded to the favourable outcome of antidepressant treatment. Deterioration of sexual functions under moclobemide treatment was infrequent and experienced by less than 3% of patients. The frequency of spontaneously reported sexual dysfunction, reported as adverse event, was lower than 0.1%. For a considerable proportion of patients included in the studies sexual function was not systematically recorded: up to 10-20% of data for variables related to sexual function were missing. Unreported sexual functioning varied in dependence of the type of function, age and gender of the patient and treatment settings. CONCLUSION: The results of the observational studies with moclobemide do not provide evidence that moclobemide induces or intensifies sexual dysfunction in depressed patients under routine daily treatment. The results also demonstrate that the assessment of sexual function in the practice is clearly influenced by the reporting attitudes of patients and physicians.

Onset of improvement under fluoxetine and moclobemide.

In a meta-analysis of the selective serotonin reuptake inhibitor fluoxetine (n = 440) and the reversible and selective monoamine oxidase-A inhibitor moclobemide (n = 437) we investigated the time course of improvement over 6 weeks for these two classes of anti-depressants. Two different methods of approach were applied: (1) repeated measurement analysis of variance in combination with regression analysis, and (2) a survival-analytical approach that allowed us to determine onset of improvement for the individual patient, to distinguish between early and late improvers, to assess the predictive value of early improvement, and to adequately process premature withdrawals. The two antidepressants of large biochemical and pharmacological differences yielded virtually identical response- and drop-out rates, and exhibited no difference with respect to the time course of improvement. Onset of improvement occurred in more than half of the patients within the first 2 weeks of treatment, and early improvement was highly predictive of later outcome. In particular, there was no indication for a delayed onset of action of antidepressants. We suggest that future studies should be standardised with respect to washout period and sufficiently dense assessments during the first 2 weeks of trial. Thus, patient samples can be subdivided reproducibly into early-, late-, partial- and non-remitters. This, in turn, may help to identify "true" drug responders, and to discover why in some patients recovery becomes "stuck". Data already held by the pharmaceutical companies should be reanalysed in this respect.

Onset of action under antidepressant treatment.

The issues of timing in antidepressant treatment are of great theoretical and practical relevance, even more so since recent meta-analyses yielded no evidence for a specific mode of action of antidepressants, which, according to the theory of delayed onset of action, is expected to emerge after 2 weeks of therapy. To address the issues of timing on a methodologically sound basis, future trials should adapt a 'longitudinal' rather than 'cross-sectional' design, standardized with respect to a washout period, baseline and first 2 week assessments. With this in mind, special attention should be paid to parameters which potentially enable the identification of placebo responders, true drug responders and patients at risk of non-improvement. Results and methods of the Zurich meta-analyses may serve as a starting point for further steps in this direction.

Delayed onset of action of antidepressant drugs? Survey of recent results.

The onset of action of antidepressant drugs was investigated on the basis of two independent multicenter, double-blind efficacy studies comparing amitriptyline (n = 120), oxaprotiline (n = 120), imipramine (n = 506) and moclobemide (n = 580) with placebo (n = 189 + 191). The samples consisted of in- and outpatients diagnosed, according to Diagnostic and Statistical Manual (DSM)-III criteria, as suffering from major depressive disorder. Measures of efficacy criteria were the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A) and the Zung Self-Rating Depression scale. By using the Sustained Relative Improvement (SRI) criterion, onset of action was determined in each individual patient as that time point in the 30 day observation period at which a 20% baseline score reduction was achieved without subsequent deterioration. Analogously, a response to treatment was defined as a 50% baseline score reduction. As expected, highly significant differences between active drugs and placebo were found with respect to the total number of improvers and responders. Significant differences between treatment modalities surfaced in the percentage rate as well as the time distribution of premature withdrawals. Yet, unexpectedly, among improvers, the time spans to onset of improvement were found to be independent of treatment modality as indicated by virtually identical cumulative percentages of improvers throughout the whole observation period. The picture was essentially the same for the HAM-A and Zung assessments, except for a significant time lag between observer- and self-ratings. In particular, our analyses revealed no evidence for a delayed onset of action under various antidepressants with large biochemical and pharmacological differences in comparison to placebo. Moreover, the early onset of improvement was highly predictive of later outcome: on average, 70% of the patients showing improvement within the first 14 days became responders. Applying survival-analytical methods, we found that differences between active treatments and placebo emerged within the first 5 days and reached a point of maximum distinction around day 14. After this time point, differences between treatment modalities remained constant until the end of the observation period. According to our data, 20-25% of the patients were, on average, 'true' drug responders, thus suggesting that the therapeutic qualities of antidepressants do not lie in the suppression of symptoms, but rather are related to their ability to elicit and maintain certain conditions which allow recovery in a subgroup of patients who would otherwise remain non-responders.

Moclobemide versus fluoxetine for double depression: a randomized double-blind study.

The efficacy and tolerability of the selective reversible monoamine oxidase A inhibitor, moclobemide (300 mg/day) and the selective serotonin uptake inhibitor, fluoxetine (200 mg/day), were compared in a six-week single-centre double-blind fixed-dose study in patients (n = 42) with double depression (DSM-III-R: dysthymia with superimposed major depressive episode) using weekly assessment on the Hamilton depression rating scale (HDRS-17 items) and clinical global impression (CGI) scale. The primary efficacy outcome measure was a decrease > or = 50% in end of treatment HDRS score, secondary measures were the mean total endpoint HDRS scores and percentages of CGI very good and good responses. Tolerability was measured by the frequency and severity of volunteered adverse events. There were no significant differences in secondary efficacy outcome measures, but more patients achieved a > or = 50% decrease in HDRS score on moclobemide (71% vs 38%, p < 0.05). The only adverse event was mild transient anxiety (n = 1) with moclobemide. The results suggest that moclobemide and fluoxetine are equally well tolerated and at least similar in efficacy in double depression. Evidence that moclobemide may be more effective requires confirmation in a larger comparative study incorporating a placebo control group.

Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia--a study group report.

The results of an open tolerability and exploratory efficacy study of bretazenil, a partial benzodiazepine-receptor agonist in hospitalized schizophrenic patients with an acute psychotic episode (DSM-III-R criteria), are presented. The duration of the study was 6 weeks, with a mandatory titration (ascending doses of 3-18 mg/day) period of 14 days. The assessment criteria for tolerability were the frequency of adverse events (including EPS), vital signs and laboratory tests. The efficacy criteria, which were only descriptively analysed, were: (a) Clinical Global Impression (CGI, percentage of "very much" and "much" improvement); and (b) change in BPRS total score (e.g. percentage of patients showing > or = 40% decrease of BPRS score at the end of the treatment). Sixty-six patients (aged 21-62 years) with acute episodes of schizophrenia of moderate to marked severity (mean BPRS score = 46.3, range 26-76) were included in the study. Of these 66 patients (68%) were reportedly non-responders (n = 10) or partial responders (n = 35) to previous neuroleptic therapy. Twenty patients (30%) terminated the trial prematurely due to therapeutic failure (no improvement or worsening after 2 weeks of treatment), 17% of patients dropped out due to other reasons (transfer to other hospitals, withdrawal of consent, intercurrent diseases) and 4.5% of patients stopped the treatment due to adverse reactions. Four patients (6%) showed early complete remission and refused to be further treated. The analysis of efficacy (intention-to-treat) revealed a sustained decrease of BPRS scores with 49% of patients showing > or = 40% BPRS score change by the end of the treatment. Forty-four per cent of patients improved "very much" or "much". Eleven patients (17%) were full responders (BPRS score decrease 75-100%) and 21 patients (32%) showed at least 40% reduction of BPRS score. The reduction of BPRS scores in completers only was 60%. All BPRS factor scores decreased in parallel and, particularly, no preferential decrease of anxiety/depression subscores was found. The analysis of tolerability showed that 59% of patients presented no complaints at all. The most frequent treatment-related adverse reactions in the remaining patients were: sedation (n = 14), dizziness (n = 4) and headache (n = 3). The results of this study suggest moderate antipsychotic efficacy of bretazenil in schizophrenic patients. They encourage further investigations of partial benzodiazepine-receptor agonists in this indication, particularly because of the excellent tolerability and lack of extrapyramidal side-effects.

Delayed onset of action of antidepressant drugs? Survey of results of Zurich meta-analyses.

The onset of action of antidepressant drugs was investigated on the basis of two independent, multicenter, double-blind studies, comparing amitriptyline (N = 120), oxaprotiline (N = 120), imipramine (N = 506) and moclobemide (N = 580) with placebo (N = 189/+191). Highly significant differences between the active drugs and placebo were found with respect to the total number of improvers and the total number of responders. In addition, significant differences between treatment modalities showed up in both the percentage rate and the time distribution of premature withdrawals. However, among improvers, the distribution of time spans to onset of improvement was found to be independent of treatment modality, indicated by virtually identical cumulative percentages of improvers over the whole observation period. This picture of treatment-independent improvement rates was essentially the same for the HAMD, HAMA and ZUNG assessments, except for a significant time lag between observerratings and self-ratings. Specifically, our analyses revealed no evidence for a delayed onset of action of various antidepressants with large biochemical and pharmacological differences when compared to placebo. The early onset of improvement was highly predictive of later outcome: on average, 70% of patients showing improvement within the first 14 days became responders. Differences between active treatments and placebo emerged within the first five days and reached a point of maximum distinction around day 14. After this time point, differences between treatment modalities remained constant until the end of the observation period. Not more than 20-25% of patients were, on average, "true" drug responders, thus suggesting that the therapeutic qualities of antidepressants do not lie in the suppression of symptoms, but rather relate to their ability to elicit and maintain certain conditions which enable recovery in a subgroup of patients who would otherwise remain nonresponders.

Antidepressants and drug-metabolizing enzymes--expert group report.

Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies.

The results of the meta-analysis of studies comparing the efficacy of moclobemide, imipramine and so-called sedative antidepressants (amitriptyline, mianserin and maprotiline) in 2416 patients are described. The results demonstrated that in agitated-anxious depressive patients (defined by HAMD factor score or HAMD item 9) a nonsedative, reversible MAO-A inhibitor moclobemide has about equal efficacy as imipramine or sedative antidepressants. All antidepressants were clearly superior to placebo, irrespective of the outcome measures applied (> 50% HAMD decrease, CGI improvement). The efficacy of antidepressants in agitated patients was unrelated to the severity of agitation and did not appear to be inferior to the efficacy in nonagitated patients. Comedication with benzodiazepines had no impact on overall efficacy of either moclobemide or other antidepressants in this patient population. Previous treatment with antidepressants, however, always negatively influenced the outcome with trial drugs, e.g., reduced their efficacy. Placebo response in agitated depressives appeared generally to be low (20-30%) and was clearly reduced with increased severity of agitation, irrespectively of how the agitation was defined.

Benzodiazepines and GABA hypothesis of schizophrenia.

Clinical and experimental studies pertinent for demonstrating the antipsychotic potential of benzodiazepines (BDZ) and the involvement of γ-aminobutyric acid (GABA) in the origin of schizophrenia are reviewed. It is shown that, due to severe methodological problems and pitfalls, placebo-controlled, double-blind studies do not permit unequivocal conclusions on the efficacy of BDZs, but neither do they completely disprove it. Furthermore, at first glance, confusing and controversial findings in animal models indicate a bi-directionality of effects of full BDZ agonists on dopamine-mediated functions, which may perhaps be explained by (i) anatomical and functional organization of the GABA-dopamine system in the nigro-striatal and ventro tegmental area, and (ii) the regional non-selectivity of action of these drugs. The recent demonstration of structural polymorphism of the GABA(A)-BDZ receptor complex and heterogeneous distribution of sets of subunits of the GABA( A)-BDZ receptor in the brain, suggests possibilities for development of partial BDZ agonists showing greater regional selectivity of action and thus potentially more specific antipsychotic action. Initial clinical results with bretazenil (Ro 16-6028), a partial BDZ agonist, in acute schizophrenia are, in this respect, an encouraging lead to be followed further.

Time course of improvement under antidepressant treatment: a survival-analytical approach.

A meta-analysis of an earlier multicenter, double-blind efficacy study comparing placebo, oxaprotiline and amitriptyline was performed in order to test the survival-analytical approach in modelling the onset of improvement and response to treatment with antidepressants. The sample consisted of moderately depressed male (n = 154) and female (n = 275) patients (aged 17-73), diagnosed according to DSM-III criteria for major depression. Of these, 120 were treated with oxaprotiline, 120 with amitriptyline and 189 with placebo. Efficacy criteria were Hamilton Depression (HAMD) and Anxiety (HAMA) and Zung Self-Rating scales. Up to eight ratings over a period of 40 days were available for analysis. The results showed that the sensitivity in discriminating between groups was substantially enhanced through the inclusion of drop-outs and consideration of the effect of time to withdrawal from the study due to lack of improvement. Withdrawal from the trial due to inefficacy occurred earliest under placebo (50% within the first 8 days), whereas less than 40% dropped out within the first 12 days under active treatments. The most interesting and unexpected finding of the analysis was that the time course of improvement among responders was independent of the treatment modality, and thus identical in all three groups. Specifically, the efficacy of any of the given treatments was reflected only by the total number of responders or nonresponders. Once triggered, the time course of recovery from illness becomes identical to that of spontaneous remissions as observed, for example, under placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

[Psychobiology of fear]. / Psychobiologie der Angst.

Fear is an affective experience and a normal psychobiologic reaction preparing the organism for defense or avoidance of threats. It is only abnormal when extent, expression and duration do not match the real danger. Three processes are elementary components of fear: 1. the perception of a signal for threat, 2. expectation, defined as inner mobilisation and augmented directional attention, 3. feeling arising from impending loss of control over the inner and outer milieu. Mutual dependence and interference between the three processes are often the basis for vicious circles in pathologic states of fear. Various aspects of fear, mainly of the anticipated fear can be explained by conditioned behaviour, a fact of significance not at last for rational psychotherapy. The form of expression and the extent of a reaction to fear is according to the hypothesis of Gray regulated by a complex functional central nervous system. The primary role of the latter consists in an inhibition of the actual behaviour in order to allow for alternative reactions adapted to the new circumstances. Intensity and quality of alarming signals ultimately determining the outcome of the reaction are mediated by neurotransmitters. These assure the correct transmission within the neuronal network and regulate the extent of activation off all neuronal cells. Three neurotransmitters are assumed to have an essential role in fear: norepinephrine, serotonin and gamma-amino-butyric-acid (GABA). The action of GABA has been documented best so far. An increase of inhibitory GABA-effects is also the main mechanism of action of benzodiazepines and benzodiazepine-like anxiolytics.

Pharmaco-EEG profile of levoprotiline: second example to discuss the predictive value of pharmaco-electroencephalography in early human pharmacological evaluations of psychoactive drugs.

The present paper forms the second part of a critical evaluation of the use of pharmaco-EEG as an instrument for assessing the profile of action of psychoactive drugs in man based on the trial results of three new psychoactive test substances. Part I described the basic principles and methodological approaches and illustrated the value of pharmaco-EEG in framing hypotheses about the therapeutic efficacy of psychotropic drugs by the example of the neuroleptic drug savoxepine. This chapter illustrates the relevance of pharmaco-EEG in the assessment of psychoactive drugs by reference to the test substance levoprotiline. Levoprotiline is the pure R-(-)-enantiomer of the racemic drug oxaprotiline, a successor to the second-generation antidepressant maprotiline. Only the S-(+)-enantiomer of oxaprotiline inhibits the re-uptake of noradrenaline. In view of the absence of any monoamine-uptake inhibiting action of levoprotiline, this drug was assumed to be devoid of an antidepressive action. This assumption, however, was disproved by observations made in clinical studies with depressive patients, in whom levoprotiline did indeed display antidepressive activity. Investigations of levoprotiline in the pharmaco-EEG model--even though being retrospective in the sequence of events--would have been able to produce objective prediction of antidepressive potential in man. The substance was tested by comparison to placebo and to the standard antidepressant imipramine in nine young, healthy male volunteers. The experimental design was a cross-over uncompleted block design with three consecutive trial days one week apart.(ABSTRACT TRUNCATED AT 250 WORDS)