[Residual symptoms and recurrence in major depressive disorder]. / Symptômes résiduels et récidive dans le trouble dépressif majeur.

The persistence of residual symptoms after treatment of a major depressive episode is found in approximately a third of all cases. Definitions of partial remission of a major depressive episode with residual symptoms are either criteriologic, like the DSM, which require a defined number of symptoms with functional effect ; or quantitative, with a score localized in a defined range on a depression evaluation scale. The persistence of residual symptoms following a major depressive episode and the risk of a new episode are closely linked as outlined in guidelines created by expert groups and savant societies as well as clinical studies done in this field. Among the risk factors to predict further depressive episodes, the weight of persisting residual symptoms may be higher than the number of previous depressive episodes. In case of residual symptoms, the therapeutic proposals rely on pharmacological or psychotherapeutic tools are essentially of two types: nonspecific potentialization of previous antidepressive treatments or additional treatment specifically targeting each patients residual symptoms. A strong consensus exists on necessity of maintaining the therapeutic efforts until disappearance of residual symptoms, this objective must be pursued in a definite and continuous way by the practitioner.

[Efficacy of escitalopram and severity of depression: new data]. / Efficacité de l'escitalopram et sévérité de la dépression: nouvelles données.

According to recent data in the literature, severe forms of depression represent almost half of all characterised episodes of depression; in view of this their treatment is a real public health challenge. According to the recommendations of various health authorities, treatment first relies on antidepressant medication. A recent meta-analysis of 12 new generation antidepressants has shown that these products are not all equivalent in the treatment of major depression, and that differences exist in terms not only of efficacy but also of acceptability. These differences in efficacy also appear true in the treatment of severe depression. Very recent publications, with a meta-analysis carried out on large cohorts of patients included in clinical trials, have shown the superior efficacy of escitalopram (which is the most active enantiomer of the racemic component, citalopram) in severe depression (defined by a total score on the MADRS scale > or =30). A pooled analysis by Kilts et al. assessed the response to treatment according to the baseline severity of the depression, under escitalopram and under six comparable products: citalopram, duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine. It showed that the rate of responders to the different treatments decreased when baseline severity increased, which agrees with the data in the literature, except for escitalopram, with which the rate of responders remained stable. The pooled analysis of Kennedy et al., that partly referred to the same studies, showed that for all the patients exhibiting severe depression, escitalopram was significantly superior to the other same six comparable products (mean estimated difference of 1.8 on the total MADRS score [p<0.0001]; a rate of 64.4 responders vs 55.8% [odds ratio=1.60, p<0.0001]; rate of remission of 47.7 vs 41.6% [odds ratio=1.39, p<0.0007]). In parallel with the statistical significance of the results, the criterion of clinical pertinence of the differences revealed between the medicinal products is highly significant. Regarding antidepressants, the criteria of clinical pertinence most frequently applied are the difference in rate of responders, the number needed to treat (NNT) and, to a lesser extent, the difference between the rates of patients in remission and the difference in the effect of treatment. According to these criteria, Montgomery and Möller (2009) assessed the clinical pertinence of the results showing the superior efficacy of escitalopram on three products: citalopram, paroxetine and duloxetine. Hence, they established this clinical pertinence for all of the depressed patients, but also in the particular case of severe depression. All these new data confirm the interest of escitalopram in the treatment of characterised depression and notably in the severe forms, with a particularly favourable efficacy/acceptability ratio.

[Severe forms of depression: the efficacy of escitalopram]. / Formes sévères de dépression : efficacité de l'escitalopram.

Severe forms of depression are a major therapeutic concern for psychiatrists. According to Health Authority recommendations, they require the systematic initiation of treatment with active drugs, and they respond less well to placebos than the less severe forms. Escitalopram, which is the most active enanthiomer of the racemic compound (citalopram), is tolerated well at the doses indicated in the marketing authorisation (10 to 20mg per day) and it is particularly effective in the severe forms of depression. Several studies have compared escitalopram to another specific serotonin recapture inhibitor (SSRI) in severe depression. In a 24-week study, 20mg per day of escitalopram, compared to 40mg per day paroxetin, demonstrated significantly greater efficacy (p<0.05) on the primary criterion (modification of the total MADRS score between inclusion and the end of the study). In this same study, the difference in favour of escitalopram increased in parallel with the increase in initial severity. In a grouped analysis of three studies versus citalopram, the superior efficacy of escitalopram also increased in parallel with the initial severity. The antidepressants, combined serotonin recapture inhibitors and noradrenalin (SRINA), might, in theory, be more effective than the SRI because of their broader mode of action. Recent data on escitalopram have invalidated this fact. In a study comparing 20mg per day of escitalopram to 225mg per day of venlafaxine during eight weeks in severely depressed patients (MADRS>30), escitalopram led to a significantly enhanced improvement (p<0.05). A grouped analysis of two similarly designed studies showed that the difference in favour of escitalopram increased at the same time as the initial severity increased. An analysis of two studies comparing 10 to 20mg per day of escitalopram to 60mg per day of duloxetine in severely depressed patients, revealed the superior efficacy of escitalopram in the sub-sample of severely depressed patients (p<0.01), with significant superiority on each of the 10 items of the MADRS taken singly. Despite the limits of regrouped analyses, all these results underline the fact that escitalopram is at least as effective as the comparators, and notably compared to the two SRINA studied, in the severe forms of depression.

[Benzodiazepines and schizophrenia, a review of the literature]. / Benzodiazépines et schizophrénie, revue de la littérature.

AIn this work, the authors have analysed the principal studies on the interest in the use of benzodiazepines in schizophrenia. The first double-controlled study concerning this question was conducted in 1961. The results of the first studies are criticisable due to the variability of the diagnostic and clinical assessment criteria, as well as to the divergences between the different conclusions. Through this review of literature, the authors wish to clarify the questions and hypothesis raised specify certain therapeutic strategies. MECHANISM OF GABA-ERGIC TREATMENTS: The analysis of the principle works on this question provides evidence on the use of benzodiazepines in schizophrenia. By fixing on their receptors, benzodiazepines facilitate GABA-ergic transmission. GABA is an inhibitor neurotransmitter. The GABA stimulation induced by benzodiazepines may be at the origin of a reduction of the pre-synaptic release of dopamine in the mesolimbic region. The GABA stimulation may also delay the post-synaptic adaptation of the dopaminergic neurons to neuroleptics. This phenomenon may enhance the activity of neuroleptics in resistant schizophrenia. Benzodiazepines would also have an effect on the mesoprefrontocortical regions where neuroleptics may be less efficient. It is interesting to note that this cerebral region is particularly sensitive to stress. This effect of benzodiazepines on the mesoprefrontocortical region might explain a preferentially beneficial effect in patients who have radiographic signs consistent with prefroncortical atrophy, although this observation remains preliminary. BENZODIAZEPINES IN MONOTHERAPY: In monotherapy their action on productive and deficient psychotic symptoms is greatly discussed and not very convincing. The main studies in the use of benzodiazepines alone ) are heterogeneous for their diagnosis criteria, their methodology and their results. The conclusions of the publications are not totally clear, and different points are to be criticized: heterogeneity of assessment criteria, heterogeneity and variability of methodology, use of non standardized scales, most of the studies are open studies, variability of benzodiazepines dose. BENZODIAZEPINES IN ASSOCIATION WITH NEUROLEPTICS: In few controlled studies, most authors have underlined ) the advantage of the association of benzodiazepines with neuroleptics. This association may act either on positive symptoms (hallucinations, delusions) or on negative symptoms. The latent period and the length of the effect of benzodiazepines in the treatment of psychotic patients remain unclear. According to certain studies, the therapeutic effect may appear in a short time, and then disappear within the fourth week. The association of benzodiazepines with neuroleptics is particularly helpful for patients with great anxiety, whether they have neuroleptic intolerance or not. There is no robust convergence about the type of benzodiazepines and their optimal dose in the treatment of schizophrenia. Their use may permit a reduction in the neuroleptic dose. They could increase the plasma concentration of neuroleptics and they might act on the mesoprefrontocortical regions where there are fewer dopaminergic auto receptors. BENZODIAZEPINES AND ANXIETY IN SCHIZOPHRENIA: States of anxiety, and in particular panic disorders that would participate in the exacerbation of psychotic symptoms, would benefit from the use of benzodiazepines. Anxiety can be considered as a major symptom of schizophrenia: insecure feelings and impressions of threatening events are frequent during schizophrenia. Interpretations or brutal hallucinations can lead to the feeling of imminent catastrophe or anxiety. Nevertheless, anxious phenomenons are under-estimated for many reasons: on the one hand, positive symptoms may hide anxiety, and on the other, the symptoms that are observed in patients treated with neuroleptics are often attributed to the neuroleptic side effects rather than linked to anxiety. Benzodiazepines and catatonia - Lorazepam has demonstrated its efficacy on catatonia. This effect seems to be specific of small doses of lorazepam (<5 mg/day). It should be compared to the effect of zolpidem in the same conditions. This prescription should be limited to acute catatonia, with no effect on chronic catatonia. Benzodiazepines and neuroleptic side effects - The use of benzodiazepines to treat some side effects of neuroleptics such as akathesia is reported by certain authors but remains little explained. They may have no effect or only small effects on tardive dyskinesia, but could reduce their incidence with the use of the smallest doses of neuroleptics in association with benzodiazepines. Safety of use - The safety of use of benzodiazepines in schizophrenia, particularly in association with neuroleptics is admitted, however recommended precautions with clozapine are to be noted. Benzodiazepine combined with clozapine clearly increases the frequency of cardiovascular and respiratory accidents. Some studies point out the risk of behavioural desinhibition and dysphoria. Their use should also be limited to patients with good compliancy, in order to avoid exacerbation of symptoms in the case of brutal interruption of the treatment. Dependency, which is an important issue in the use of benzodiazepines, seems much lesser in schizophrenia than in personality disorders and anxiety. Conversely, some studies point out the benefits of benzodiazepine use in schizophrenia, with their efficacy in the treatment and prevention of drug abuse. Finally, benzodiazepines contribute to the establishment of a good patient-doctor relationship, and may guarantee enhanced treatment compliancy.

[Management strategies for major depressive episodes as a function of initial response to an SSRI or SNRI antidepressant: results of the ORACLE survey]. / Stratégie de prise en charge d'un EDM en fonction de la réponse précoce à un antidépresseur IRS ou IRSNA: résultats de l'enquête ORACLE.

OBJECTIVE: The main aim of the major depressive episode treatment is to obtain a complete remission. However, partial remission (persistence of residual symptoms) is a frequent outcome of major depressive episodes, concerning approximately half of the patients who were responders to the treatment. An inadequate treatment response after three weeks of treatment is considered by the ANAES recommendations as a potential reason to modify the treatment regimen. The primary objectives of this survey were to describe the therapeutic strategies implemented in subjects treated as outpatients for a major depressive episode following evaluation of the initial response to an SSRI or an SNRI antidepressant and to assess by a naturalistic way the impact of these strategies on the extent of remission at three months. The secondary objective was to determine, by multivariate analysis, others factors able to influence the remission. METHODS: This prospective observational survey concerned 2 138 patients treated by community psychiatrists (n=582) and presenting a major depressive episode in the context of a recurrent depressive disorder. Patients were assessed at inclusion and at Weeks 3, at Week 6 and at Week 12. Changes in score on the Hamilton Depression Scale (Ham-D) and CGI severity between inclusion and Week 3 and improvement scores were evaluated. The therapeutic strategies after evaluation were described. Remission was defined as a score of 1 or 2 on the CGI-improvement scale; a treatment response at Week 3 was defined as a decrease of at least 50% in the Ham-D score. The physician also provided an overall rating of satisfaction with the treatment at Week 3. RESULTS: Data from 1 974 patients were analysed. The mean age at inclusion was 42.7 years, 70% of the patients were women; the mean age at first episode was 32.2 years, the average time since the last episode was 3.6 years. The mean Ham-D score at inclusion was 23.6 +/- 5.8. At Week 3, 29.1% of patients were considered treatment responders. The antidepressant dose was subsequently increased in 10.2% of responders compared to 36.3% of non-responders. When the physician rated the treatment response as unsatisfactory, the dose was increased in 56% of cases. At week 12, 83.7% of patients were in remission as defined by the CGI; according to physician judgement, 45.7% were in complete remission and 43.3% in partial remission. According to the literature, the existence of an early response to the treatment predicted a total remission at Week 12 (69.1% of the treatments responders at Week 3 were in complete remission at Week 12, vs 35.7% of the treatments not-responders). CONCLUSION: These results underline the professional practices in private community psychiatric practice in France. At Week 3, posology increased for only 36.3% of the patients, whereas it is one of the therapeutic strategies recommended by the ANAES. Participating physicians relied on their subjective judgement about initial treatment response when making decisions about treatment strategies rather than by psychometric scores. At Week 3, 29.1% of patients were considered treatment responders according to the change in Ham-D score, compared to 57.3% whose treatment response was considered satisfactory by the physician. The decision to increase the dose was more closely associated with subjective perceptions of satisfaction than with psychometric rating scale scores, despite psychometric evaluation was systematic in the ORACLE survey, what is not the case in usual practice in France, except for clinical research. In addition, this study confirms an important data for the clinician: there is a correlation between early response to the treatment (Week 3) and complete remission at the end of the acute phase of treatment (Week 12).

[Antidepressants consumption in the global population in France]. / Résultats d'une enquête sur l'usage des antidépresseurs en population générale française.

The consumption of antidepressant seems to be in France higher than in comparable countries, as well as the overall consumption of healthcare and medications. In Western countries, in recent years, the use of antidepressants has regularly increased, mainly due to the use of serotoninergic antidepressants. In France, in a week, the prevalence of antidepressant use in the overall population increased from 1.7% in 1992 to 3% in 1995. This survey addressed the overall population in the form of a representative sample focusing on subjects who indicated, at the time they were consulted, that they were taking an antidepressant. The study aimed to determine the circumstances of prescription: prescriber file, reason for prescription, type of medication prescribed, match between the prescription and the product indications stated in the marketing authorization, prescription duration and reason for discontinuing treatment. Methodology - The first stage consisted in forwarding a letter to a panel of 44 000 subjects aged 15 years or more and representative of the French population. The aim was to achieve a cross-sectional description of the population taking antidepressants. The response rate was 82% (36 036 subjects). The subjects who stated that they were taking an antidepressant were re-contacted by telephone by an interviewer trained in the use of the Composite International Diagnostic Interview - lifetime (CIDI), exploring depression and anxiety diseases with a view to potential diagnosis as per DSM criteria. Longitudinal follow-up over 8 months from the initial screening was evaluated using a monthly questionnaire on the time course of antidepressant consumption. Results - Out of 20 000 households, comprising 44 000 people aged over 15 years, 1 333 people were taking an antidepressant or had taken one in the previous 4 weeks. The sex ratio of the antidepressant consumers was 3 women to 1 man, amplifying the known sex ratio with respect to depressive disorders. The mean age of the subjects taking an antidepressant at time t was 51 years. Lifestyle and socioprofessional category did not seem to influence antidepressant consumption. Somatic comorbidity was present in 60% of antidepressant consumers. Among the consumers of antidepressants at time t, 45% were taking a selective serotonin reuptake inhibitor (SSRI). The two products most widely prescribed in that class were fluoxetine (30% of the subjects taking an antidepressant at time t) and paroxetine (10% of the subjects taking an antidepressant at time t). The other SSRIs accounted for the remaining 5%. Thirty-nine percent of the consumers were taking a tricyclic antidepressant: clomipramine in 16% of cases, amitriptyline in 14%, and other tricyclic antidepressants in 9%. Lastly, 20% of the consumers were taking an antidepressant that was neither an SSRI nor a tricyclic antidepressant. Only 4% of the patients were concomitantly taking 2 antidepressants: single-agent therapy is in line with the recommendations of the various expert groups. In the survey, 9 antidepressant prescriptions out of 10 were written by an open-care practitioner, and 1 out of 10 by a hospital physician. For 60% of the subjects, the antidepressant treatment was prescribed by a general practitioner. General practitioners prescribe less tricyclic antidepressants and more SSRIs than specialists. The main reason for prescription reported by the patient was depression (57% of cases); followed by a state of anxiety or stress (15% of cases). In 10% of cases, the consumer stated that the reason for treatment was not psychological. Sixty-two percent of subjects presented with, or had presented with, a mood disorder as per M-CIDI (major depression, mood disorder, or a combination of the two) and 14% an isolated anxiety disorder. Twenty-five percent of the subjects on antidepressants did not fulfill all the M-CIDI criteria for any diagnosis. Among the people receiving antidepressants, 54% had a CIDI diagnosis in strict compliance with the marketing authorization indications for the product considered. One quarter (25%) presented with a diagnosis of a characterized psychiatric disease, outside of the marketing authorization indications for the product taken. This finding reflects misuse or use on the basis of published data not incorporated in the marketing authorization. The dosages were in line with those stated in the marketing authorization for the disease considered in almost 99% of cases for the subjects on paroxetine and fluoxetine, but for only 22% of cases for the subjects on tricyclic antidepressants. Tricyclic antidepressants would therefore appear to be frequently inappropriately in terms of proportions that would be ineffective: half of the subjects on clomipramine were taking a dose less than or equal to one third of the minimum recommended dose. Conclusion - This survey shows that the point-prevalence of antidepressants in the global population in France is about 3.5%. Women consume more antidepressants than men. SSRIs are the most widely prescribed antidepressants. The survey findings point out the discrepancies between official indications, such as the ones issued by the regulatory authorities, and the physicians' prescribing practices.

[Effects of escitalopram on anxiety symptoms in depression]. / Effets du escitalopram sur les symptômes anxieux dans la dépression.

Selective serotonin reuptake inhibitors, the antidepressants most widely prescribed today, exert specific action against various anxiety disorders and have an excellent acceptability profile. In addition, anxiety problems are commonly seen in depression, in the form of either characterised anxiety disorders or associated anxious symptoms. Such symptoms of anxiety result in increased risk of suicide and appear to be associated with development of more severe and chronic depressive disorders. Because of the adverse effects associated with anxiolytics, in particular benzodiazepines, their indications have been restricted. Consequently, first-line drug therapy for anxiety symptoms associated with depression involves selection of an antidepressant having anxiolytic properties. Specific serotonin reuptake inhibitors are commonly favoured at present since they have a less pronounced sedative effect than the tricyclic antidepressants (e.g. amitriptyline, maprotiline). Escitalopram, the active enantiomer of citalopram, has demonstrated efficacy and rapidity of action upon depressive symptoms seen in major depressive episodes. Global analysis of three studies comparing citalopram and escitalopram with a placebo in depressive disorders allowed specific investigation of the activity of these molecules upon the anxiety component of depressive disorders. Anxiety was quantitatively evaluated using item 6 (inner tension) of the MADRS, and for two of the three studies, using the anxiety sub-score of the HAM-D as well as the HAM-A total score. The results for the two active molecules demonstrate significant superiority in comparison with the placebo. Furthermore, in the case of escitalopram, this improvement appeared significant as of the first week of treatment (p<0.05); by the end of the second week of treatment, the degree of significance was even more pronounced (p<0.001). The tolerability profile of these two active substances was very good. These studies thus demonstrate the efficacy of escitalopram against anxiety symptoms associated with depression, together with particularly interesting rapidity of action. Use of an antidepressant with proven activity against anxiety accompanying depression avoids the need for co-prescription of tranquillizers, which themselves are not devoid of adverse effects.

[Treatment adherence in the recurrent depressive disorders]. / Observance thérapeutique dans les troubles dépressifs récurrents.

It is difficult to achieve treatment compliance in recurrent depressive disorders. This disease involves a combination of psychiatric and depressive disorders and is a chronic condition: all of the characteristic features of the disease constitute an obstacle to compliance. Compliance in depressive patients may be improved through various approaches. Information provided to patients, which is widely encouraged today both by doctors and by the regulatory authorities, must be as complete as possible; it must include discussion of factors of that favor depression, as well as the logical basis of the management approach proposed. Furthermore, the best guarantee of compliance is probably maintenance of euthymia by means of suitable treatment. Long-term therapy with antidepressants and the institution of a mood regulator (valproate in particular) have both been shown to be efficacious and significantly superior to placebo. Published studies show that continued treatment with an antidepressant can reduce the risk of depressive relapse noted during long-term follow-up (between 18 months and 5 years) by at least 50%. This has been demonstrated for both tricyclic antidepressants and specific serotonin reuptake inhibitors. The need for continued long-term administration of the dosages with proven efficacy during the acute episode has been demonstrated for imipramine but also appears to have been verified for SSRIs. Even when depressive relapse occurs, it is often less severe if the antidepressant treatment has been continued. Although first-line preventive therapy generally comprises long-term continued administration of the antidepressant, use of mood regulators may occasionally be proposed: valproic acid is generally preferred over lithium assaults on the ground of safety. However, there are few studies demonstrating the preventive efficacy of structured psychotherapy against recurrence of depression. Good treatment compliance entails major benefits: the prescribed treatment is able to reduce the risk of recurrence of depression, and in all probability also reduces subsequent vulnerability to depression, even after treatment discontinuation, as emphasized by the kindling theory of R. Post.

[Depression and manic-depressive disorders]. / Dépression et maladies maniaco-dépressives.

The two major subtypes of manic-depressive illness are bipolar disorder and recurrent major depressive disorder. Biological data strongly indicate that a significant genetic factor is involved in the development of manic-depressive illness. But, stressful life events, environmental stress and premorbid personality factors may also be involved in other important etiologic factors. Some research data indicate that cyclothymic disorder and temperamental disorders may be considered as mild forms of bipolar disorders so called "subaffective disorders". The identification of clinical or biological features reflecting the severity of the major depressive episode is very important in regard of the high potential for suicide of the illness.

[Calcium antagonists and lithium in preventive treatment of manic-depressive disorder]. / Inhibiteurs calciques et lithium dans le traitement prophylactique de la maladie maniaco-dépressive.

Recent advances in knowledge about calcium's role as an intracellular regulator allow to broaden understanding of possible pathophysiologic mechanisms in affective disorders. An hypothesis emerge that bipolar illness arise from disorders in calcium-regulated functions. Given this hypothesis, some authors propose to describe the common profiles of action of the different mood-stabilizers: all the neural mechanisms that are hypothesized to explain various psychopharmacological treatments of bipolar illness involve functions that are critically controlled by calcium. Moreover, in every instance, a known action of lithium on calcium-dependent processes could account for lithium's prophylactic results. Similarities exist between the action of lithium and calcium antagonists like verapamil and nimodipine. From these considerations the hypothesis emerge that calcium antagonists could be an alternative pharmacological agent in the maintenance treatment of bipolar illness. Calcium antagonists have been found useful in this indication by a number of investigators. Given the safety and relative lack of side effects of calcium channel blocking agents, their potential efficacy in mood disorders, it is concluded that calcium antagonists may be an alternative choice in prophylactic treatment for bipolar illness, especially in patients who cannot be treated with lithium or carbamazepine. There is evidence for using verapamil at 240 to 320 mg a day, in 2 to 4 times. Some studies suggest that the association of lithium with calcium antagonist resulted more effective than lithium alone or calcium antagonist alone in the reduction of episodes of affective disorders. However, concomitant administration of a calcium channel antagonist and lithium present adverse interactions (lithium toxicity, cardiovascular accidents), probably because of synergistic toxic effects. Therefore, authors advise care in monitoring patients receiving the combination of these medications.