[How to assess curative and/or preventive effects of psychotropic drugs?] / Comment évaluer l'effet curatif et/ou préventif des psychotropes ?

Proving the efficacy of a psychotropic drug is a medical, scientific and ethical need. Psychotropic drug development is now a highly complex process, which takes several years and which is very expensive. It involves multiple steps of preclinical and clinical pharmacological refinement and testing. Methodology of studies to prove curative or preventive effect of psychotropic drugs is well codified. Preclinical studies include pharmacokinetic data, toxicology and performance in various animal models of pathology. Clinical phases are centered on randomized controlled double blind trials for demonstrating efficacy and safety/tolerability. This methodology follows strict criteria to avoid bias and to prove internal and external validity of the results. All the results from randomized controlled trials or RCTs lead to different levels of evidence of Evidence-Based Medicine (EBM): gold standard is RCTs while the lowest reference is clinical case or expert opinion. However, it is possible to level criticism at these data issued from RCTs. The main matter is that studies do not reflect the healthcare reality in daily life. For these reasons, a real debate between evaluation of efficacy and effectiveness is acute. Effectiveness refers to the overall effects of psychotropic drugs in naturalistic conditions. Furthermore, analysis of costs and financial benefits are more and more important from social and economic points of view. Official agencies and health insurances look after them very carefully. This article deals with these issues and provides examples using data from the international literature. These examples are drawn from RCTs, naturalistic studies, meta-analysis, pharmaco-economic studies and concern neuroleptics, antipsychotics, antidepressants, and mood-stabilizers.

[Inclusion criteria and rating scales for RCTs in Psychiatry. The future of qualitative studies]. / Quels patients inclure et quelles échelles utiliser dans un essai clinique ? Les études qualitatives en perspective.

An inventory on the two critical dimensions that structure the Randomized Controlled Trial in Psychiatry, namely the definition of inclusion criteria for eligible patients for testing and the choice of psychometric methods of pathology assessment and its evolution during the experiment, considers the importance of increasingly numerous and precise international recommendations. Taking into account the formal constraints of industrial, questioning the cultural differences of the methodological approach of the tests, meeting the requirements of feasibility and ever increasing security, frequent cumbersome procedure often contrasts with the modest nature of the results. A better definition to include patients in randomized trials is desirable and it asks to return to the clinic studying the expectations of patients and their response to the therapeutic situation. Excessive standardization otherwise required for ensuring the objective nature of the assessment hampers the collection of original and varied clinical features of importance in the further definitions of indications. On the way to a resumption of the single case study, we can expect from qualitative methods applied to small groups of subjects, optimization principles of patient selection for the upcoming randomized trial and greater chance to address the relevant details of clinical response to the therapeutic situation. This is what has led to the discovery of psychotropic drugs and which is involved in the various modalities of the qualitative approach. For example, and beyond the exploration of clinical drug effects, the study of the experience of psychiatric inpatient care in the Healing Garden, conducted on a small group and on the basis of the narrative analysis of their experience, notes several operating thematic dimensions: a reduction in the perception of symptoms of the disease, the impression of regaining a foothold into reality, the interest of a differently perceived doctor-patient relationship, the advantage of renewed power to act and the recognition of the importance of support from others, patients recovering somehow « vitality ¼ of touch with reality. This suggests the possibility to establish an appropriate rating scale for such a specific therapeutic situation and to provide a more accurate and efficient recruitment for a comparative objective demonstration. Moreover, this construction of meaning reinforces the therapeutic benefit of treatment in Healing Garden and offers new dimensions for research.

[How may practitioners interpret the results of clinical trials?] / Comment le praticien doit-il interpréter les résultats d'un essai clinique ?

To correctly interpret the results of a randomised controlled trial (RCT), practitioners have to spot bias and other potential problems present in the trial. Internal as well as external validity of the trial are linked to the presence of such bias. The internal validity is ensured by a clear definition of the objectives of the trial. The number of patients to be included in the trial is calculated on the basis of the main objective of the trial and more precisely on the basis of the primary endpoint selected to assess the efficacy of treatment. This is the best way to ensure that the statistical significance of the result may have a clinical relevance. Internal validity depends also on the process of patients selection, the methods used to ensure comparability of groups and treatments, the criteria employed to assess efficacy, and the methods for the analysis of data. External validity refers to subjects that have been excluded from the trial, limitations of RCTs, as well as the coherence and clinical relevance of the trial. Internal validity has to be fueled by external validity.

[Interpersonal psychotherapy from research to practice]. / La thérapie interpersonnelle de la recherche à la pratique.

THEORETICAL BACKGROUND: Interpersonal therapy (IPT) is a brief, structured psychotherapy initially intended to treat adult depression that was developed in the 1970s and manualized in 1984 by G. Klerman and his team. Two main theories served as a basis for its design: Bowlby's attachment theory and communication theory. Klerman theorized that tensions and problems in interpersonal relationships (i.e. disputes) cause psychological distress in vulnerable individuals that may lead to a major depressive episode. Clinical and epidemiological studies have shown that an insecure attachment style is strongly associated with lifetime depression. Severe depressive episodes have been correlated with avoidant attachment in women. THERAPY STRUCTURE AND TECHNIQUES: IPT is based on the hypothesis that recent or ongoing disturbances in interpersonal relationships either trigger or follow the onset of mood disorder. In practice, IPT assists patients in analysing their interpersonal relationship modes, correlating their relational states with their mood and in learning to use better communication. Resolving difficulties in interpersonal relationships through the use of better communication skills promotes the improvement of depressive symptoms. Klerman identified four interpersonal areas that seem to be highly correlated with depressive episodes: grief (a close and important personal relation who has died), interpersonal disputes (conflicts with significant people such as a spouse or another close family member), role transition (significant life changes such as retirement, parenthood or chronic and invalidating illness) and interpersonal deficits (patients who have limited social contacts and few interpersonal relations). Classically, IPT is planned around 12-16 weekly sessions. During the initial sessions, the therapist will explore all existing interpersonal relations and any significant dysfunctions, both recent and ongoing. Following this interview, the area the patient considers as driving the current depressive episode will be designated as the focus of therapy. Evaluation of depressive symptoms by a quantitative measure (i.e. Visual Analogue Scale) and qualitative measures (activity, pleasure, quality of life) reoccurs at each session. During the intermediate sessions, therapy uses current situations and events in the designated area that particularly affect the patient's mood. Coping, communication and decision-making skills are gradually improved through a number of techniques. These include non-directive and directive exploration, clarification, encouragement of affect, and communication analysis. The therapeutic relationship is empathetic and encouraging of all progress the patient makes. The final phases close the therapy and help the patient to plan future actions and improvements. CLINICAL TRIALS OF IPT AND DEVELOPMENTS: Several controlled clinical trials in adult populations have demonstrated the efficacy of IPT in treating Major Depressive Disorder (initial and recurrent episodes). It has been recommended as an appropriate treatment option in several guidelines. It can be provided in individual, couple or group formats. There remains an ongoing discussion of the efficacy of monthly maintenance sessions in recurrent depression. Since its conception, clinical trials have explored its use in specific populations such as adolescents and the elderly. IPT has also been the object of trial in other disorders such as post-partum depression, bipolar disorder, social phobia and eating disorders. CONCLUSION: This article reviews the basic principles and objectives of this therapeutic model. Theoretical concepts and results from research are also discussed. The approach is briefly described and the various therapeutic phases are discussed. Clinical trials have shown that IPT is effective in treating major depressive disorder in a wide variety of populations. Further trials are necessary to determine its efficacy in other psychiatric disorders.

[Affective disorders: News in chronobiological models]. / Troubles affectifs : actualité des modèles chronobiologiques.

Good news on chronobiological models of affective disorders are coming from a therapeutic innovation in the field of antidepressive action. Coming back to fundamentals by reconsidering the importance of the role of biological rhythms impairment in dysthymic pathology, a new interest bored on studies exploring short periodicities, so-called "ultradian" ones, on the basis of pharmacodynamics in the concept of therapeutic "window" of administration. The priority of circadian rhythms due to the major external biological desynchronization in depression, as well as the importance of sleep and alertness pathology, the spectacular relief of the depressive mood upon sleep deprivation, and the strong reduction of sleep need in mania, delayed exploration of ultradian exaltation of harmonic circadian components, marking a "buzz" of rhythmic structure and calling a "chronobiotic compound" which would be able to apply a "reset" to the temporal organisation. Another return to the origin leads to the experimental genomics, informing nor the "depressivity" but manic pathogenesis, in a mouse gene model which queries on the share of addictive and affective disorders.

[Gene-environment interactions in affective disorders]. / Interaction gènes-environnement dans les troubles affectifs.

Kindling and behavioural sensitization were probably the first among the animal models of affective disorders, to suggest that genes-environment interactions were likely to be involved in the pathophysiology of these disorders. Cross-sensitization among stressors, drugs of abuse and illness episodes was deemed to be supported by the induction of a series of transcription factors, such as the proto-oncogene c-fos that subsequently alter gene expression by binding at DNA sites and inducing mRNAs for substances that may exert effects over long time periods. This was an anticipation of epigenetics which is currently defined as a functional modification to the DNA that does not involve an alteration of sequence. Epigenetic modifications are most commonly regulated by DNA methylation and histone acetylation which are usually associated with the silencing and activation of gene transcription, respectively. In animal models, it was shown that parents can actively remodel epigenetic marks, and thus affect patterns of gene expression in the offspring, whereas environmental adversity decreases parental investment in the offspring and thus alters phenotypic development. In line with this, some laboratories have sought to identify changes in gene expression in post mortem brain samples of humans with affective disorders. Finally, gene-environment interactions have been directly studied, both in animals and humans, by testing how a functional polymorphism in candidate genes would moderate the influence of stressful life events on behavioural expression. Interesting results have been found and replicated for unipolar depression, however date are scarce for bipolar disorder. Findings from these studies allow the building of more sophisticated models for unipolar and bipolar genetics.

[Affective disorders, antipsychotics and mood stabilizers: Therapeutic innovations]. / Troubles affectifs, antipsychotiques et thymorégulateurs : innovations thérapeutiques.

Management of bipolar disorder has undergone many revisions in recent years as new agents and treatments have been developed and studied with variable success. In conjunction with the advent of novel therapies and indications, there has been an increase in the understanding of the phenomenology and neurobiology of bipolar disorder that has made the classification and management of the illness necessarily more sophisticated. However, there remains a significant delay of 8 years in detecting and diagnosing bipolar disorder, and a further need to improve treatments. However, this paper has emphasized the need to be aware of recent advances and the emerging uses of new pharmacological treatments in the management of bipolar disorder. It has also highlighted the need for tailoring management to the individual. In particular, the successful treatment of bipolar disorder requires achieving prophylaxis and preventing relapse. In this regard, maintenance therapy is of paramount importance, and thus the tolerability of agents needs to be considered throughout treatment and should be factored into all management decisions. At the centre is the individual with bipolar disorder and the need to maintain a healthy therapeutic relationship. However, it is important to note that the evidence synthesized in this paper serves only as a guide to the management of bipolar disorder and that, in clinical practice, all treatment recommendations require contextual interpretation, the consideration of local factors and the consultation of additional resources.

[Bipolar affective disorders: Models and assessment of psychological treatments]. / Troubles affectifs bipolaires : modèles et bilan des approches psychothérapeutiques.

Psychological therapies dedicated to bipolar patients have attracted major interest and many publications have been devoted to them in the last five years. The efficiency of Psychoeducation, Cognitive and behavioral therapy, Behavioral family therapy and Interpersonal and Social Rhythm Therapy, have specially been focused on. These approaches share a common background of psychoeducation and are closely linked with the transnosographical model from Zubin and Spring as well as basic behavioral and cognitive technical requirements. All these therapies focus on medication adherence, regular lifestyle, early recognition of relapse and early pharmacologic intervention. There are some differences between advantages from each approach, but the overall effect is positive in enhancing medication adherence and preventing manic relapses, and also in preventing depressive episodes and improving quality of life. These robust and corroborating results should probably be integrated in future guidelines for the management of bipolar disorders.

[Interpersonal and social rhythm therapy (IPSRT)]. / Thérapie interpersonnelle et aménagement des rythmes sociaux (TIPARS) : du concept anglo-saxon à l'expérience française.

Bipolar disorder is common, recurrent, often severe and debiliting disorder. All types of bipolar disorder have a common determinant: depressive episode. It is justify to propose a psychotherapy which shown efficacy in depression. Howewer, perturbations in circadian rhythms have been implicated in the genesis of each episode of the illness. Biological circadian dysregulation can be encouraged by alteration of time-givers (Zeitgebers) or occurrence of time-disturbers (Zeitstörers). Addition of social rhythm therapy to interpersonal psychotherapy leads to create a new psychotherapy adaptated to bipolar disorders: InterPersonal and Social Rhythm Therapy (IPSRT). IPSRT, in combinaison with medication, has demonstrated efficacy as a treatment for bipolar disorders. IPSRT combines psychoeducation, behavioral strategy to regularize daily routines and interpersonal psychotherapy which help patients cope better with the multiple psychosocial and relationship problems associated with this chronic disorder. The main issues of this psychotherapy are: to take the history of the patient's illness and review of medication, to help patient for "grief for the lost healthy self" translated in the french version in "acceptance of a long-term medical condition", to give the sick role, to examinate the current relationships and changes proximal to the emergence of mood symptoms in the four problem areas (unresolved grief, interpersonal disputes, role transitions, role déficits), to examinate and increase daily routines and social rhythms. French version of IPSRT called TIPARS (with few differences), a time-limited psychotherapy, in 24 sessions during approximatively 6 months, is conducted in three phases. In the initial phase, the therapist takes a thorough history of previous episodes and their interpersonal context and a review of previous medication, provides psychoeducation, evaluates social rhythms, introduces the Social Rhythm Metric, identifies the patient's main interpersonal problem area, and contractualizes the therapy. In the second phase, the therapist focuses work with patient toward regulating the patient's daily routines as well as resolving the interpersonal problem areas relevant to episodes (mainly interpersonal disputes and role transitions). In the third or terminaison phase, the therapist evaluates efficacy of the therapy, enhances the patient's independent functioning and develops strategies for relapse prevention. The further maintenance phase suggests differents strategies as maintenance therapy or focused intensive interventions on specific topics.

[Prodromes of schizophrenia recurrence]. / Les prodromes des rechutes schizophréniques.

Schizophrenic disorders are chronic disorders usually characterized by relapses alternating with periods of remission. A better understanding of the course of schizophrenic disorders is available with the models of psychotic vulnerability and the neurodevelopmental hypothesis. The relapses have numerous severe aspects, clinical, biological and conduct to a bad prognosis. A relapse prevention constitutes a major issue in regard of public health. A relapse prevention is possible with identification of relapse prodromal signs (or early signs of relapse). The relapse prodromal signs are often aspecific but remain stable in each patient. These relapse prodromal signs are similar to the initial prodromal signs, as well as in symptomatology than as their chronologic apparition. Specific psychoeducation strategy allows for each patient to learn its own stressful events and its own prodromal signs of relapse, as well as onset of each prodromal symptoms. A pilot study conducts to a psychoeducative program of relapse prevention centered on learning about prodromal symptoms and validation of a relapse prodromal signs questionnaire.

Antipsychotics and the risk of diabetes: a general data review.

Recently, attention has focused on a potential link between schizophrenia and diabetes, with speculation that this potential association is stronger in patients who are prescribed atypical antipsychotics. Pharmacoepidemiological studies can help to evaluate this potential association. Source data on the incidence of diabetes in patients treated with antipsychotics is available in the FDA MedWatch database, prescription claims databases and other patient registries. These data indicate that antipsychotic drugs may increase the risk of developing diabetes and that there may be an interaction with age. However, current data are insufficient to accurately assess potential differences in the risk of diabetes between users of individual antipsychotic medications. In addition, antipsychotic treatment-emergent diabetes has several distinct features, notably relating to age of onset, gender ratio, rate of deterioration of glycaemic control, and independence from initial treatment emergent weight gain. Nonetheless, guidelines for the control of risk factors for diabetes developed for the general population appear to be applicable to patients with schizophrenia.

Clonazepam in acute mania: time-blind evaluation of clinical response and concentrations in plasma.

This study was performed to evaluate the optimal doses and clinical efficacy of clonazepam as a first-line drug in acute mania, as well as to determine its effective plasma concentrations. Clonazepam was administered orally to 11 newly admitted inpatients. On day 0, the loading dose was titrated upward according to the clinical global impression; the maintenance dose was calculated with intent to maintain the plasma level that had been achieved after initial dose escalation. Clinically based dose adjustments were allowed on days 4 and 7. Manic symptoms were scored on days 0, 4 and 14 according to a time-blind procedure; clonazepam plasma levels were measured by HPLC. On day 14, there was a significant decrease in manic symptoms and 66.7% of the patients who completed the trial were markedly improved. Steady-state plasma levels of clonazepam were significantly correlated with daily doses (rs = 0.795, P < 0.005) and therapeutic concentrations ranged between 6.5-83.9 micrograms/l. At the onset of therapy, the clinically titrated loading dose resulted in plasma concentrations within the narrow range of 18.9-34.0 micrograms/l. These results support the potential value of clonazepam in the short-term management of acute mania; the initial control of agitation was achieved with plasma drug levels in a remarkably narrow range as compared with the further control of mania.

An imidazopyridine anxiolytic alters glucose tolerance in patients: a pilot investigation.

We have recently shown that compounds with high affinity for peripheral-type benzodiazepine receptors inhibited glucose-induced insulin secretion in vitro. We therefore performed an oral glucose tolerance test in anxious inpatients treated with the imidazopyridine derivative alpidem, which has been shown to display high affinity for these binding sites. The test was performed before and after 1 week of daily administration of the drug. As compared with pretreatment values, a significant alteration of the insulin response to glucose was observed. It is suggested that daily administration of alpidem, at therapeutically effective doses for the treatment of anxiety, may alter glucose tolerance.

Pilot investigation of thyrotropin-releasing hormone-induced thyrotropin and prolactin release in anxious patients treated with diazepam.

Benzodiazepines have been reported to inhibit thyrotropin (TSH) and prolactin (PRL) secretion in response to stressful and pharmacologic stimuli in experimental animals. The current study investigates basal and thyrotropin-releasing hormone (TRH)-stimulated TSH and PRL release in anxious patients treated with diazepam. Six hospitalized patients having generalized anxiety or adjustment disorder with anxious mood (DSM III-R criteria) were treated during 1 week with diazepam (mean daily dose 33.3 mg). TRH testing was performed comparatively before and after 7 days of diazepam administration (with 250 micrograms protirelin and blood sampling at 15-min intervals over 60 min). Steady-state plasma levels of diazepam and its metabolite nordazepam (desmethyldiazepam) were determined by high-performance liquid chromatography. After 7 days of diazepam treatment, basal plasma levels of TSH and PRL were not affected compared with pretreatment values. Similarly, the time-course of TRH-induced TSH release was not modified by the treatment. By contrast, there was a trend to decrease in the TRH-induced PRL release, and the decrease in the PRL response to TRH on day 7 was significantly correlated with plasma nordazepam concentrations (rs = 0.943, p = 0.02). These preliminary results suggest that benzodiazepines, at therapeutic doses for the treatment of anxiety, may alter TRH-induced PRL release in humans.

A double-blind comparison of clonazepam and placebo in the treatment of neuroleptic-induced akathisia.

The present study was designed to investigate the efficacy of clonazepam in neuroleptic-induced akathisia. Twelve patients were treated during 2 weeks with clonazepam or placebo in a double-blind randomized design. Akathisia was scored by an independent rater before and after treatment, as well as 1 week after medication withdrawal. Clonazepam (0.5-2.5 mg/day) induced a significantly higher reduction in the akathisia scores than placebo (p < 0.05). One week after stopping the drug, there was a partial but significant relapse in the treated group as compared with controls, in whom the symptoms remained stable. In addition, the clinical improvement was significantly correlated with the daily dose of clonazepam (rs = 0.827; p < 0.002). These results support the potential usefulness of clonazepam in the treatment of neuroleptic-induced akathisia and suggest an optimal daily dose in the range of 10-40 micrograms/kg.

[Role of carbamazepine in the treatment of endogenous psychoses. Results of an open study]. / Place de la carbamazépine dans le traitement des psychoses endogènes. Résultats d'une étude ouverte.

The authors report the results of an open trial which aims at specifying the clinical profile of responders to carbamazepine among a population of twenty patients aged from fifteen to seventy, suffering from endogenous, schizophrenic, affective psychoses and paranoid states according to the criteria of the ICD 9. The trial points out a proof of Kishimoto's criteria and a preferential acting of the molecule on schizo-affective psychoses and mixed affective states. The results are interpreted according to psychopathological concepts from the Vienna school that highlight the clinical profile of the responders.

[Plasma MHPG, peripheral noradrenergic marker and hormonal plasma levels of cortisol-T3-T4-TSH in depressive syndromes]. / Contribution á l'étude du MHPG plasmatique marqueur noradrénergique périphérique et des taux plasmatiques hormonaux de cortisol-T3-T4-TSH dans les syndromes dépressifs.

Based on the hypocatecholaminergic hypothesis in the depressive syndromes, this survey on 30 depressed patients compared to 21 control patients, attempts to state exactly the potential interactions between the noradrenergic system and the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid neuroendocrine axis. The biological indices used during this survey are: total plasmatic MHPG, the basic plasmatic cortisol, the thyroid hormones T3, T4, free T4, and the TSH. The results of this survey reveal a significative increase of the basic plasmatic cortisol among the depressed patients, including dysthymics, a decrease of the plasmatic MHPG during major depressions, and a significant fall of the total T3 among depressed men, as well as some correlations between the different axes, the interpretation of which remains "ticklish".

Concurrent high-performance liquid chromatographic measurement of loxapine and amoxapine and of their hydroxylated metabolites in plasma.

The dibenzoxazepine neuroleptic loxapine, its N-demethylated metabolite amoxapine, and their 7- and 8-hydroxymetabolites were measured simultaneously in plasma by reversed-phase high-performance chromatographic method. An original liquid-liquid extraction procedure was performed, consisting in coextraction of the substances together with a water-miscible solvent (acetonitrile) by a non-water-miscible solvent (toluene). The substances were separated on a 5-microm CN 25-cm column, and eluted with a mobile phase consisting of acetonitrile-acetic acid 0.5 N (30:70) and hexylamine (0.05%). They were detected by ultraviolet spectrophotometry at 310 nm. Clozapine was used as internal standard. Linearity was demonstrated in the range of 10 to 250 microg/l, and detection limits were found to be 3.5 to 6.3 microg/l according to the substance. Within-day repeatability ranged from 2.7% to 6.5%, and between-day reproducibility ranged from 0.9% to 20.2%. The extraction procedure provided a mean absolute recovery of 51.1% (range, 40.7% to 58.6%) with a mean coefficient of variation of 4.2%. This technique was applied to the concurrent determination of plasma concentrations of the compounds in 10 patients administered loxapine 75 to 600 mg daily. Steady state plasma levels of loxapine were significantly correlated with oral doses (n = 10, r = 0.858, p < 0.002). In conclusion, the method proved to be a convenient and reproducible procedure allowing the simultaneous measurement of loxapine, amoxapine, and their metabolites in patients.