New statistical proposals to evaluate the benefit/risk ratio of long-term treatment of depression: application to a one-year double-blind study comparing medifoxamine with fluoxetine.

The aim of this study was to determine the benefit/risk ratio of long-term treatment with medifoxamine, a non-tricyclic, non-monoamine oxidase inhibitor agent, and fluoxetine in patients with acute depressive episode and at high risk of relapse and/or recurrence. The study involved a 12-month double-blind, randomised, parallel-group design with a multicentric trial setting conducted by 64 participating physicians. 155 and 158 patients of either gender, aged between 18 and 70 years, were allocated to fluoxetine and medifoxamine, respectively. All patients had an acute depressive episode defined by the presence of at least five of the DSM III-R criteria with a minimal score of 25 on the Montgomery and Asberg Depression Rating Scale (MADRS). All subjects had at least one previous documented depressive episode in their medical history. The main outcome criterion consisted of good therapeutic response defined by a sustained 50% reduction of the Clinical Global Impression (CGI) score combined with the absence of any serious or troublesome (i.e. intensity motivating study discontinuation) events. In the fluoxetine and medifoxamine groups, respectively, 45.2% and 43% of the randomised patients completed the 12-month follow-up period with no major differences between groups regarding the reasons for treatment withdrawal. With each treatment 58% of the patients reached at least a 50% decrease in their CGI score, with no differences on the evolution of the MADRS, Hamilton Anxiety Rating Scale (HARS), the Self Rating Depression Scale of Zung (Zung scale) and Scott depression visual analogue scale (VAS) scores on average. According to the main efficacy criterion, 26% of the patients in the fluoxetine group were considered as responders compared with 36% in the medifoxamine group (p = 0.047). When only serious adverse effects were considered in combination with CGI scores to define response rates, the respective percentages were in favour of medifoxamine but the difference (45 vs 53%) was not significant. Results with medifoxamine were better in the elderly whereas, with fluoxetine, best responses were observed in younger patients. In conclusion, medifoxamine was an active and well tolerated drug in the continuation and maintenance treatment of depression. Its benefit/risk ratio appeared to be superior to fluoxetine, but this difference was mainly based on the occurrence of less minor adverse effects, a potential advantage not sufficient to favour better compliance with long-term therapy. Nevertheless, efficacy and tolerance of medifoxamine merits further evaluation in specific elderly populations.

Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia.

BACKGROUND: Amisulpride is a substituted benzamide with high selectivity for dopamine D2 and D3 receptors. The purpose of the study was to evaluate the effect of 100 mg amisulpride in patients with predominantly negative symptoms of schizophrenia. METHOD: This was a multi-centre, randomised, parallel-group, double-blind study. Patients received either amisulpride (100 mg/day) or placebo over a six-month treatment period. RESULTS: A total of 141 patients were included, 69 received amisulpride, 72 placebo. Fifty-eight patients (41%) had received neuroleptic treatment prior to inclusion. The percentage of amisulpride patients completing the study (55%) was significantly higher than that with placebo (32%), and drop-out rates due to lack of efficacy were 27% with amisulpride and 47% with placebo. All efficacy assessments were statistically in favour of amisulpride compared with placebo. The overall incidence of extrapyramidal symptoms was comparable in both groups; only five patients started anti-Parkinsonian treatment during the study (one in the placebo and four in the amisulpride group). CONCLUSION: Amisulpride is effective in the medium-term treatment schizophrenic patients with predominantly negative symptoms.

Factorial structure of the 17-item Hamilton Depression Rating Scale.

The Hamilton Depression Rating Scale was applied to 60 depressed inpatients diagnosed using the Composite International Diagnostic Interview. The information to rate the scale was obtained with a semistructured interview to standardize the scale administration method. Items were factorized using principal components analysis with Varimax rotation. Three factors were obtained with the simulation method, accounting for 47% of variance. The first includes the core symptoms of depression. The symptoms of patients having an isolated mood disorder were compared with those having comorbidity with other diagnoses. The comorbidity did not affect the first factor but modified the second factor (anxiety) and the third factor (insomnia).

[Social adjustment and depression: value of the SAS-SR (Social Adjustment Scale Self-Report)]. / Adaptation sociale et dépression: intérêt de l'échelle SAS-SR (Social Adjustment Scale Self-Report).

The Social Adjustment Scale Self-Report (SAS-SR) is a simple and inexpensive method, which allows the routine assessment of the patient's social adjustment, especially in the case of depression. Compared with other scales based on an interview with the patient, the SAS-SR is more sensitive to change in the patient's clinical status. The SAS-SR is a useful method as part of the detection of even mild depressions, regular aftercare evaluation of out-patients or as an outcome measure in longitudinal studies. A French version of the SAS-SR is now available and is currently under evaluation in a large-scale randomized therapeutic trial.

Effects of antidepressants on cognitive functions: a review.

The widespread use of antidepressants since the late 1950s and especially the ambulatory treatment of the majority of depressive patients raises the issue of the state of knowledge of the effects of these drugs on cognitive function. This review aims at synthesizing information about differential effects of antidepressants on cognitive function to facilitate good prescription. The first part of this review tries to summarize the main tasks used to explore global reactivity, attention, memory and psychomotor performances. The second part of this work presents the differential cognitive effects of antidepressants with a discrimination between substances which have a sedative impact, antidepressants with no cognitive effect, and drugs which seem to have a positive cognitive action. The differenciation is established for single and repeated administration, for healthy volunteers and depressed subjects. For each substance, the dose, the tasks selected and cognitive effect are discussed and the question of the real benefit of this cognitive impact is raised. The specificity of cognitive effects of antidepressants related to age and to the combination with alcohol are also tackled. Then the discussion raises the difficulty and the biases encountered to perform neuropsychological studies and particularly evaluation of cognitive effects of antidepressants. Finally the conclusion of this review gives some advice to select and prescribe antidepressants according to their cognitive effects.

[Biological vulnerability to depressive disorders]. / Vulnérabilité biologique aux troubles dépressifs.

For some 20 years, numerous research teams have sort to identify specific biological markers for depression. There have been three main stages in this search, each of which was characterized by progress in the technologies then available. The first stage involved evaluation of the activity of known neurotransmitters, involving assay of concentrations of precursors or catabolites, as well as measurement of the activity of enzymes regulating synthesis and catabolism, rate of up-take and storage. The second phase involved use of specific radioactive ligands which bind to neuronal membranes and receptors. This allowed in vivo exploration of the central nervous system in man. Finally, the third stage has involved a functional approach, both cellular and systemic, based upon the dynamic measurement of biological response to stimuli of central origin. While the first two approaches are of course a rather indirect reflection of central nervous system function, the third allows assessment interactions between the various systems. The countless laboratory studies carried out in depression have not provided useful etiologic, diagnostic or therapeutic results, and currently, far more attention is given to the interactions between the various neurotransmitter systems than to each system taken individually. Numerous studies have been carried out to assess interactions between the neurological, immunological and endocrine systems, and abnormal immunological parameters have been reported. Similarly, the endocrine disorders seen in depression could be attributable to a disorganization of the hippocampal-hypothalamic-adrenalin axis due to accumulation of stress. The vulnerability could also be due to preclinical sensitization, as described in the "kindling" model. Post gave particular importance to the role of biochemical modifications induced by repetitive stress. Long-term modifications could involve changes in transcription factors involved in protein synthesis, leading to long-term changes in peptides which, in turn, could lead to neurobiological modifications in the limbic system, a sort of "depression memory" rendering patients far more vulnerable to subsequent episodes. Finally, we would note that the identification of a gene for susceptibility to disorders of mood in some families is only a first step towards the characterization of the protein produced by the gene; this protein should in turn either modulate or produce a signal or a message of some sort. Furthermore, the genetic component itself could act via environmental or relational factors involved in the genesis of the depression. Finally, it is very important to bear in mind the great plasticity of neuronal systems, which are continuously subject to adaptation and modulation phenomena.

[Application of a structured interview guide adapted to 4 depression scales]. / Application d'un guide pour l'entretien structuré adapté à quatre échelles de dépression.

The authors present the development and the application of a structured interview guide for 4 depression scales: Hamilton Depression rating scale 17 items (HDRS-17), Montgomery-Asberg Depression rating scale (MADRS), Widlöcher Depressive Retardation Scale and also a fourth scale designed to evaluate the symptoms other than depression core symptoms (based on Depression and mania rating scale of P. Pichot). The final version of the guide was tested with 60 french depressed inpatients. This guide provides clinical information that permits the rating of the 4 scales in approximatively 45 minutes.

[Effects of antidepressants on cognitive functions. Review of the literature]. / Incidence des antidépresseurs sur les fonctions cognitives. Revue de la littérature.

In this review the authors propose to study the impact of antidepressants on attention, memory and motor functions in healthy volunteers and depressed patients on single and long-term administration. After reviewing the principal cognitive functions, we examine the actual investigation means to conclude that the Critical Flicker Fusion Test (CFFT) is one of the most drug-sensitive tests. It permits a categorization in: sedative antidepressants that in single administration lower CFFT; compounds with no effect on CFFT and no deleterious cognitive effect; and finally substances that raise CFFT and may have psychostimulating properties. On single administration amitriptyline is the most sedative antidepressant on attention or motor level. It seems to produce negative effects on memory level. However, experimental trials give contradictory results. Imipramine in single administration also has sedative effects on memory and car driving capacity. However divergent results of experimental trials do not allow any conclusions of a clearcut negative cognitive effect. Memory impairments with imipramine appear at administration levels of 150 mg. Mianserin has a sedative impact on attention and motor level at low doses (10 mg). Among the tricyclics, nortriptyline has a highly dose dependent sedative effect that has been shown on attention tests (Time Reaction:TR, Digit Symbol Substitution Test: DSST). Among non-tricyclic compounds, doxepine lowers attention and motor performances. Maprotiline (75 mg) lowers CFFT and has a dose dependent effect. Trazodone also has a negative impact on attention tests. Finally viloxazine lowers CFFT but does not impair other attention or motor tests on a 100 mg doses. Buspirone, lofepramine, midalcipran and zimelidine are antidepressants with no effect on CFFT and do not have any positive or negative cognitive effect. On the other hand nomifensine, paroxetine and fluoxetine raise CFFT in healthy volunteers on single administration. Improvement of CFFT performances was found in an isolated manner for nomifensine and paroxetine on 30 mg doses with no other memory or motor effects. MAO-Inhibitors do not impair attention or motor function; thus moclobemide has no negative impact on memory, attention or car driving tests. Cognitive impact of antidepressants in depressive patients seems the same with those of healthy volunteers on single administration. In long-term administration antidepressants have different effects in healthy and depressed subjects. In healthy volunteers cognitive effects of most compounds are normalized after the second week of treatment. However, attention and motor performances with amitriptyline are normalized after 3 weeks of treatment. Sedative motor or cognitive effects of imipramine do not exceed 8 days.(ABSTRACT TRUNCATED AT 400 WORDS)

[Use of pharmacological data in the choice of antipsychotic drugs]. / Usage des données pharmacologiques dans le choix d'un antipsychotique.

The choice of antipsychotic drug should be based on experimental data from biochemistry and animal pharmacology, according to the targeted clinical effects. However, owing to the lack of good animal models of mental disease only the clinical approach can validate the antipsychotic efficacy of a drug. Within the theoretical frame of dopaminergic activity in schizophrenia a specificity of the various neuroleptics according to the four dopaminergic structure is evidenced through cellular electrophysiological studies. Classical provisional pharmacology of antipsychotics uses in animals on the one hand naturalistic observation tests, and on the other hand interactions vis-à-vis behaviours induced by stimulating dopaminergic agents, as amphetamine and apomorphine. Differential analysis of antipsychotic effects on each of those behaviours allows to discriminate between the various neuroleptics and to refine their pharmacological profile, specially to predict a disinhibitory action with some of them. Progress in the identification, localisation, number modification of target receptors of different neurotransmitters as well as the biochemical response to their stimulation by agonist or antagonist allows to delineate more precisely the neurobiochemical action of antipsychotic drugs. On top of antidopaminergic D2 effect, anti D1 effect begin to be investigated. More over the role of antiserotonergic 5-HT2 and central anticholinergic actions seems to be important in the "atypical" aspect of some neuroleptic drugs. More recently, contributions from molecular biology made it possible to clone and to synthetize five subtypes of dopaminergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

[Nonspecific factors and variations in biological parameters studied in biological psychiatry]. / Facteurs non spécifiques de variations des paramètres biologiques étudiés en psychiatrie biologique.

Some studies found no connection at all between biological parameters and mental illness. There are many reasons for the discrepancies: populations and parameters investigated as well as the method used, widely differed. The discrepancies observed, could also be partly due to several non-specific factors such as age, sex, hormonal status, circadian or circannual variations, and washout period. The authors report here some data gathered in the course of a psychobiological research program on healthy volunteers. Their results indicate that human plateler MAO activity shows an apparent menstrual cycle related variation [3H] IMI binding in human platelets shows circadian variations in summer and some antidepressant drugs have a residual effect on serotoninergic parameters during one month. These studies oblige investigators to be cautious when interpreting biological data in psychiatry. Ideally longitudinal studies should be implemented at the various stages of mental illness.

[Informed consent of patients in psychiatry. Consequences in biomedical research]. / Consentement éclairé du malade en psychiatrie. Conséquences sur les recherches bio-médicales.

After the Huriet law (December 20th 1988) a free, informed and explicit consent procedure has become compulsory in biomedical research. This obligation is particularly uneasy with mental patients. Stricto sensu it excludes from research all psychotic patients unable to become "informed" and to "consent" to something. Moreover age, understanding, the quantity of informations, the personality of investigators and above all patients' suggestibility may be biases when recruiting subjects willing to participate in a trial. It is only after marketing that a thorough knowledge of the scope of a new drug will be established in terms of efficacy. Furthermore, patients informed about the possible ingestion of a placebo may become less responsive to the placebo as well as to the active drug. In a double-blind trial the physician will be unable to explain the effects experienced during the treatment period. The Huriet law should be adjusted taking into account the specificity of the field of psychiatry and being aware of the treatment and investigational problems within the framework of psychiatric emergencies.

Lack of correlation between plasma DOPEG and urinary MOPEG levels in depressed patients.

Twenty-four-hour urinary excretion of 3-methoxy,4-hydroxyphenylethyleneglycol (MOPEG) and levels of free and conjugated plasma 3,4-dihydroxyphenylethyleneglycol (DOPEG) were measured in 56 depressed patients to find a possible correlation between these two peripheral indices of cerebral noradrenergic activity. Plasma DOPEG was measured at 9:00 AM on the same day that urine was collected for the measurement of MOPEG. All depressed patients were diagnosed as having affective disorders according to DSM-III. No correlation was found between plasma free or conjugated DOPEG levels and urinary MOPEG output. This lack of correlation was found in the total sample of depressed patients (56), in 45 patients diagnosed as having major depressive episodes, and in 24 depressed patients diagnosed as major depressive with melancholia. The authors discuss the significance of this lack of correlation between two peripheral indices of central noradrenergic metabolism.

Decrease in plasma levels of 3,4-dihydroxyphenylethyleneglycol in major depression.

Plasma levels of free and sulfoconjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of norepinephrine, were measured in a group of 45 hospitalized patients presenting a major depression and a group of 45 healthy subjects, matched for sex and age. Compared to healthy subjects, depressed patients had significantly lower plasma levels of free and sulfoconjugated DOPEG. The ratio of free over conjugated DOPEG was not statistically different in the two groups. The reduction of plasma DOPEG levels in the depressed patients did not appear to be related to the duration of drug-free period and was similar in males and females. There was no statistically significant correlation between plasma DOPEG levels and total score on the Hamilton Rating Scale for Depression. Finally, plasma DOPEG levels did not differ in unior bipolar patients. The present data provides further evidence for a reduced CNS noradrenergic transmission in major depression.

[Study of noradrenaline metabolism in depressed patients by the determination of plasma dihydroxyphenylethylene glycol]. / Exploration du métabolisme de la noradrénaline chez les déprimés par le dosage du dihydroxyphényléthyléneglycol plasmatique.

The plasmatic levels of free, sulfoconjugated and total dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of noradrenaline, have been measured in thirty DSM3 major depressive inpatients and in thirty healthy controls matched for sex and age. DOPEG levels have been measured by a radioenzymatic assay. Almost fifty per cent of depressed inpatients were D.S.T. non suppressors, thirteen patients were unipolar and thirteen bipolar. Plasmatic DOPEG levels were significantly lower in depressed patients as compared to healthy controls despite a wide interindividual range of DOPEG values. However, the ratio of free over conjugated DOPEG was not statistically different in the two groups. DOPEG levels were slightly higher in the female population of healthy volunteers but not in the depressed patients. In the healthy volunteers, but not in depressed patients, there was a trend for free DOPEG to increase and for conjugated DOPEG to decrease with age. There was no statistical correlation between the DOPEG levels and Hamilton Depression Scores. Also plasmatic DOPEG values were not different in uni or bipolar patients and in DST suppressor or DST non suppressor inpatients. The significance of the decrease of plasmatic DOPEG levels in depressed patients is discussed: this diminution may reflect a deficiency in noradrenaline metabolism in CNS or else may be attributed to other factors e.g. alteration in circadian rhythms, differences in motor activity, in level of anxiety, in sleep and feeding behaviors; cotreatment with benzodiazepine and opiate compounds; monoamine oxidase activity.

[The value of the measurement of intra-erythrocytic lithium in the bio-clinical surveillance of lithium therapy (author's transl)]. / Intérêt du dosage du lithium intra-érythrocytaire dans la surveillance bioclinique de la lithiothérapie.

THe correlation between red cell lithium concentration and signs of neurotoxicity have been reported in the literature by a great majority of authors. A deficiency in the lithium-sodium counter-transport mechanism may be responsible. Measurement of blood lithium levels only is not always sufficient to identify in the laboratory patients showing signs of intolerance. The three cases reported here indicate the limitations of the measurement of plasma lithium levels and the perfect correlation between neurological signs and erythrocyte levels. In vitro studies of transmembrane ion exchanges should make it possible to undertake an investigation before starting treatment in order to identify the risks of cellular toxicity.

Influence of route of administration on haloperidol plasma levels in psychotic patients.

Haloperidol plasma concentrations were determined in psychotic patients to whom the drug was given by three different routes of administration (i. v. perfusion, intramuscularly and orally). When measured 15 hours after the last administration, a significant difference (p < 0,001) was found in the steady state plasma concentration between the oral and the i.m. route. The values were higher after intramuscular administration and were subject to less interindividual fluctuation than after the oral. The reduction in plasma levels after oral administration in respect to i.m. were in accordance with the bioavailability of haloperidol. The opportunity of switching from oral to intramuscular treatment is discussed.