[Interest of scopolamine as a treatment of major depressive disorder]. / Intérêt d'un traitement par scopolamine dans les troubles dépressifs.

INTRODUCTION: The number of patients with depression in the world is 350 millions according to estimates. The search for new treatments, particularly in forms of resistant depression, is necessary given the growing number of patients experiencing treatment failure and resistance. Scopolamine, an anticholinergic antimuscarinic molecule, is one of the treatments under evaluation. It falls within the assumptions of cholinergic disruption of the pathophysiology of depression, at different levels (genetic, receptorial [muscarinic and glutamate receptors], hormonal, synaptic…). In 2006, a pilot study made to evaluate the role of the cholinergic system in cognitive symptoms of depression found unexpected results regarding the antidepressant effect of scopolamine in depressive patients. Since that time other studies have been conducted to evaluate the benefits of treatment with intravenous injections of scopolamine. OBJECTIVE: Our main objective was to evaluate the interest of scopolamine as an antidepressant treatment in depressed populations. METHODS: We conducted a literature review with the aim of assessing the effectiveness of treatment with scopolamine in uni- and bipolar patients with depressive symptoms. The protocol consisted of two injection blocks (each block consisting of three injections spaced fifteen minutes apart within three to five days) of active ingredient or placebo crossover. The selected patients were between 18 and 45years and had the DSM-IV major depressive disorder or bipolar disorder criteria. Regarding the methods of measurement, the primary endpoint was the reduction in scores of the Montgomery Asberg Depression Rating Scale (MADRS) with a total response defined by a decrease of more than 50 % of the score and remission corresponding to a MADRS score<10. Seven sessions of evaluations were performed. RESULTS: The published results are promising in terms of efficiency with rapid antidepressant effect, a total response rate ranging from 59-64% and a remission rate of between 37 and 55% in uni- and bipolar patients, which persists at least 15days. The treatment was well tolerated by patients with relatively mild and transient side effects the most common being the sensation of sleepiness that was also found in the placebo group. There were no serious side effects such as heart failure or confusion. In terms of mood, there was no becoming manic or hypomanic even for bipolar patients. CONCLUSION: The results are encouraging, but there is concern for the moment because of the few studies, so to date there is little data on the subject including medium and long term.

[Etiopathogeny of the delusion of pregnancy using a literature review: Role of hyperprolactinemia and application of the theory of abductive inference]. / Étiopathogénie des délires de grossesse à partir d'une revue de la littérature : rôle de l'hyperprolactinémie et application de la théorie de l'inférence abductive.

INTRODUCTION: Delusions of pregnancy are not well known. The delusion of pregnancy is defined as the belief of being pregnant despite factual evidence to the contrary. The clinical picture is heterogeneous (duration, mechanisms, topics and pre-existing psychiatric disorders). Several causes have been proposed to explain the occurrence of the delusions of pregnancy: cenesthetic theory, hyperprolactinemia, polydipsia and psychodynamic conflicts. Hyperprolactinemia is an interesting hypothesis (physiologic increase during pregnancy and similar manifestations in the course of gestation). The abductive inference theory is a probabilistic model that can clarify the role of hyperprolactinemia in the delusions of pregnancy. The purpose of this paper is to study the role of hyperprolactinemia in the delusions of pregnancy using a literature review. The abductive inference model is used to specify the etiopathogeny of this pathology. METHODS: A research in Medline, Sudoc, BIUM and PSYLINK using the following key words "delusional pregnancy" or "delusion of pregnancy" and "hyperprolactinemia" was conducted. RESULTS: Three articles (case reports) about delusions of pregnancy associated with hyperprolactinemia were found. The cases have some similitudes. First of all, they have similar chronology: delusion appears at the same time as hyperprolactinemia and resolves with biological normalization. Secondly, hyperprolactinemia is always caused by a neuroleptic (haloperidol, olanzapine, risperidone). Concerning pre-existing disorders, a psychiatric pathology for each case was found (schizophrenia, schizo-affective disorder and bipolar disorder). Chronology, reproductivity and reversibility are strong arguments to involve hyperprolactinemia in the delusions of pregnancy (Bradford Hill criteria). Furthermore, this association is biologically plausible: physiologic increase during pregnancy (gestational signal), similar symptoms to those during pregnancy and the role in parental behavior (parental signal). Nevertheless, not everyone with hyperprolactinemia will develop a delusion of pregnancy; the interaction is more complex (non linear); the theory of abductive inference clarifies this relationship. THEORY OF ABDUCTIVE INFERENCE: Abductive inference is a probabilistic model whose goal is to explain the occurrence of delusional beliefs. The first factor is the abnormal data. The second factor is the cognitive process (abductive inference), which uses Bayes' theorem to select the most likely hypothesis to explain the abnormal data. In the delusion of pregnancy, abnormal data is the hyperprolactinemia, signal of gestation without pregnancy. Hypotheses in order to explain this signal are then produced (pregnancy or no pregnancy). In the second part, probabilities associated with each hypothesis, given the hyperprolactinemia, are compared. Since hyperprolactinemia is a gestational signal, the pregnancy hypothesis is most likely. Probabilities associated with each hypothesis without taking hyperprolactinemia into account are compared (prior probability). Since any element of reality indicates a pregnancy, the absence of pregnancy is most likely. In the last step, the posterior probability is calculated using the first two comparisons. The probability associated with the pregnancy hypothesis (taking into account hyperprolactinemia) is relatively higher than the probability associated with the no-pregnancy hypothesis (without taking into account hyperprolactinemia). So, the posterior probability associated with the pregnancy hypothesis is more likely than the posterior probability associated with the no-pregnancy hypothesis. Thus, the subject believes in a pregnancy. CONCLUSION: The research and the treatment of hyperprolactinemia must be conducted when faced with a delusion of pregnancy.

Descriptive study of the occupational outcome of bipolar patients.

INTRODUCTION: The purpose of this study was to describe the occupational outcome of bipolar patients 3 years after being hospitalized in a psychiatry department, and the determinants of this outcome. METHODS: One hundred and one bipolar patients consecutively hospitalized between 1st January 2002 and 31st December 2003, were recruited. Their occupations and medical items were assessed at baseline from the medical records and reassessed 3 years later, using a questionnaire on their work and treatment, and a quality of life scale. Occupational outcome was compared by univariate and multivariate analyses. RESULTS: Of the 101 patients initially recruited, 36 were excluded and 34 were lost to follow-up. Among the 31 bipolar patients included in the study, 58.1% were working in 2003 and 54.8% were working in 2006. The presence of a personality disorder was significantly associated with a poorer occupational outcome and a lower rate of "return to work". CONCLUSION: More than half of a population of hospitalized bipolar patients was employed. The presence of a personality disorder appeared to be a pejorative factor for "return to work", although other studies are needed to define the factors that determine the occupational outcome of bipolar patients.

[A new patient focused scale for measuring quality of life in schizophrenic patients: the Schizophrenia Quality of Life Scale (SOL)]. / Création et validation d'un autoquestionnaire mesurant la qualité de vie de patients souffrant de schizophrénie: l'échelle schizophrenia quality of life (SOL).

UNLABELLED: RATIONALE/OBJECTIVE: Quality of Life (QOL) has been recognized as an important measure of the outcome of patients by clinicians and policy makers in Mental Health. The emerging consensus in the health field that personal values and the patient's preferences are important in monitoring the quality of medical care outcomes makes it even more important to assess the patient's perspectives. Unfortunately, there is little consensus about what constitutes QOL or how to measure it, particularly in psychotic patients. The objective of this study is to report the stages of development and validation of a QOL questionnaire based on issues pertinent to patients with schizophrenia. METHOD: During a first phase, identical pattern were identified among interviews (conducted by psychologists) of schizophrenic patients (DSM IV, n = 100), mental health staff (n = 20) and families (n = 20). The data gathered in the first phase were discussed and organized, by 25 experts, into a structure that made up the skeleton of the scale (133 items, 17 factors). Based on a prospective epidemiological study conducted with 337 French psychiatrists, a validation analysis of structural and psychometric proprieties was performed. Finally reliability of the scale was assessed by a second test/retest (D0, D7) study (n = 100). RESULTS: A total of 686 schizophrenic, schizophreniform or schizoaffective patients (DSM IV) were included. Internal consistency analysis identified 14 factors (74 items), all with a Cronbach's alpha of at least 0.75: professional life (0.95), affective and sexual life (0.92), illness knowledge (0.90), relationship (0.92), life satisfaction, (0.87), coping with drugs (0.79), drugs impact on the body (0.87), daily life (0.83), family relationship (0.81), future (0.88), security feeling (0.84), leisure (0.87), money management (0.76) and autonomy (0.75). Construct validity was confirmed (Pearson test) using established clinical (Brief Psychiatry Rating Scale and Clinical Global Improvement), social (Psychological Aptitude Rating Scale) and generic quality of life (Functional Status questionnaire) measures, correlation coefficient was significant for all factors but 2 in the BPRS (illness knowledge and coping with drugs) and 3 in the CGI (illness knowledge, coping with drugs and life satisfaction). Lastly, test/retest indicated high reliability for each factor (p < 0.001), the lower correlation coefficient (r) was 0.526. CONCLUSIONS: The Schizophrenia Quality Of Life-scale (SOL), based on a patient's point of view approach, is an efficient, multidimensional instrument designed for the measurement of the consequences of schizophrenia on individuals' lives.

Effects of haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers.

The effects of a typical neuroleptic, haloperidol (1 and 2 mg orally), of an atypical neuroleptic, amisulpride (50 and 100 mg) and of a placebo on motor and cognitive skill learning were assessed in 60 healthy volunteers using repeated testing on the Tower of Toronto puzzle. Subjects were asked to solve three blocks of eight trials and, at distance from drug administration, a fourth block. The puzzle was connected to a computer in order to obtain a precise timing of individual moves. Two components of cognitive skill learning were assessed, the ability to learn to solve the puzzle and the acquisition of a problem-solving routine. Subjective feelings of effort and automatisation of the task were assessed using a questionnaire. Like placebo-treated subjects, neuroleptic-treated subjects were able to acquire a motor skill, to learn to solve the puzzle and to acquire a routine. However, haloperidol 2 mg-treated subjects needed significantly more moves to solve the puzzle in blocks 3 and 4, some of them having routinised a non-optimal solution. A significant cognitive slowing was observed in the haloperidol 1 mg group in block 4. The performance pattern and verbal reports suggested that haloperidol impaired the higher cognitive functions such as the ability to shift from one strategy to another and/or to assess one's performance accurately, possibly leading to the development of compensatory strategies. The only deleterious amisulpride effect was a cognitive slowing in block 4, which was observed in the lower dose group.

Bilateral ECT and autobiographical memory of subjective experiences related to melancholia: a pilot study.

The aim of this pilot study was to systematically assess the influence of bilateral, sine wave ECT on autobiographical memory of past subjective experiences related to melancholia. Twenty-one inpatients who met DSM-III-R criteria for a Major Depressive Episode, Melancholic Type, were included in the study. Twelve patients were treated by ECT (12 treatments), antidepressants and benzodiazepines; the comparison group comprised 9 patients treated by antidepressants and benzodiazepines. The Structured Interview Guide for the HDRS (SIGH-D) was used at admission and after the ECT treatment to standardize data collection about subjective experiences related to the depressive episode. Memory of subjective experiences related to melancholia was assessed with free-recall, cued-recall and recognition tasks. In addition, a free recall of events of the day on which the patients came to the hospital for their treatment was administered. These tasks were administered 1 week after the last treatment in the ECT-treated group and 4 to 6 weeks after the beginning of the treatment in the comparison group. Free-recall, cued-recall and recognition performances were significantly lower in the ECT-treated group than in the comparison group. No significant correlation was found between memory of events related to hospital admission and memory of subjective experiences related to depression. In conclusion, bilateral, sine wave ECT impairs autobiographical memory of subjective experiences related to melancholia in subjects tested 1 week after completion of a course of ECT.

[Anxiety and cognition disorders]. / Anxiété et troubles cognitifs.

Anxious subjects present attentional disorders that are manifest with an increased bias towards threatening contents stimuli. In tasks derived from the Stroop task (such as emotional Stroop, a variant of the classic Stroop task) congruence between anxious themes or manifestations and stimuli content induces information processing changes leading to a slowness of response speed. In this case, results are similar to those obtained in signal detection tasks either when information is visually or auditorily presented. In anxious subjects an inconscious activation provoked by anxiogenic words is observed. Because such activation is independent from the semantic content of the words, an emotional priming has been hypothesized. Berck formulated an hypervigilance theory according to which anxiety provokes a selective distractibility regarding non pertinent stimuli. Such attentional selectivity would be responsible of a cognitive vulnerability in anxious subjects. State but not trait anxiety induces working memory performances deficit. On the bases of Baddeley's working memory framework, Eysenck proposed that anxiety uses part of the limited attentional capacity, placing the subject in a dual task situation. In that, he has to cope with pertinent information and anxiety generated information. If anxiety leads to better performance in simple tasks by recruiting motivational capacities, in tasks with high information content, anxious subjects performances are impaired. Changes in the long-term memory do not seem to fit with the theoretical models based on cognitive impairment observed in patients suffering from depressive states. Anxious subjects presented a memory bias towards anxiogenic information in implicit memory tasks. But experimental data are still too searce to describe implicit performance of anxious subjects and more systematic studies are therefore needed.

[Therapeutic action lag time and resistance to treatment]. / Délai d'action thérapeutique et résistance aux traitements.

The need for an antidepressant with a short time to action onset is justified by the need to reduce the risk of suicide, the patients suffering and the cost of the disease. How can a difference in action lag time be demonstrated? An appropriate methodology specific to the question must be developed. The selection of sensitive scales is an initial requirement enabling detection of early onset alleviation under treatment. Response criteria must first be defined in order to clearly answer the question "what is a short time to action onset?". Frequent scale determinations (Hamilton Depression Rating Scale, MADRS) at the start of the study is indispensable. The literature recommends at least two determinations per week over the first two weeks of treatment. Statistical methods of the survival curve type are the most appropriate for demonstration of a between-treatment difference in terms of time to action onset. Some authors consider that only placebo-controlled studies enable a difference in terms of time to action onset to be concluded. For other authors, neglecting studies versus reference products seems prejudicial to demonstrate a difference between the times to action onset of reference products and new products (Montgomery, 1997). The literature on time to action onset is not very rich. An initial study comparing amineptine and fluoxetine concluded the time to action onset was shorter for amineptine (Daléry et al., 1992). The value of the booster effect of pindolol in combination with serotonin reuptake inhibitors is controversial. Venlafaxine seems to accelerate the response (day 4) and be superior to a comparator (Clerc et al., 1996; Guelfi et al., 1995). The study conducted by Guelfi, in France, in patients presenting with severe depression was designed to evidence the efficacy of venlafaxine in melancholia. In 1996, Benkert published a double-blind study comparing venlafaxine and imipramine in severe depressions. Both studies stressed the rapid action onset of venlafaxine (between day 4 and week 2) in severe depressions. The number of patients presenting with a characterized state of depression and not responding to initial antidepressant treatment has been estimated at 30%. While there is no formal consensus on the definition of resistance to treatment, certain authors define responders as those showing a 50% reduction in the total score on the Hamilton Depression Rating Scale (HAM-D) or MADRS. Helmchen (1991) considers that resistance can only be suggested after two successive single-agent treatments with antidepressants with different action mechanisms have failed. A number of factors must be considered with respect to the genesis of treatment failure: mainly psycho-organic, psychoaffective and psychosocial factors.

[Definitions and recommendations for studying the delay of antidepressant action. Part 3: methodological aspects]. / Définitions et recommandations pour l'étude du délai d'action des antidépresseurs.

AIMS: To provide a journal publishing all literature relevant to the time of response to antidepressants, in order to find out any existing consensus which might bring in fine recommendations for a thorough study of the concept. Three sections corresponding to 3 articles surveyed by the Encephale deal with the pharmacological, clinical, and metho-dological aspects. METHOD: A group of experts (see conclusion) was trained on the initiative of the authors, following a think-talk at a meeting of scientific learned societies (FUAG and AFPB in particular). Dr Sophie Banzet, from the Boehringher-Ingelheim Laboratories, attended the meeting as a partner supporting this project. The article tries to give the most faithfull coverage of the main topics discussed by the group of experts, allowing each author to highlight his own contribution after the rereading of his text by the two other authors of the group. Are also included in the analysis the major studies published in the literature at the date when the present article was submitted. RESULTS AND CONCLUSION: There are no unequivocal criteria to assess or identify the time of response to antidepressants on a pharmacological level. In fact, the criteria depend on the symptomatic impact of the antidepressant while depression cannot be defined as a single-symptom pathology. The criteria retained for assessment depend on the chosen definition which is: either quantitative (patients profiles global method), or qualitative (sympto-matic approach). One should discriminate between the assessment of the time of response and the stage proving the efficacy of the antidepressant. The threshold proposed for efficacy is based on the values of the thresholds used in clinical tests and in literature, as well as those commonly accepted by the various drug agencies. Choosing the variable for the response to antidepressants must take into account the popu-lation of patients responding to treatment. A consensus on the choice of comparators can be observed in studies on the time of response to antidepressants: using a placebo is necessary. The active reference product depends on the population concerned. The statistical methods which have been used, in particular the survival analysis methods are very useful indeed but they entails loss of information and must be completed by tests which, though simpler, allow simpler conclusions (such as c(2)). Lastly, the experimental level, which aims to assess the time of response, remains by far the most difficult part. It is still unsolved and the study aiming to prove efficacy. We have not included the considerations on this particular point as this would require an article in its own right. The cognitive symptoms belonging to the DSM IV diagnosis criteria in major depressive periods can help to build new tools.

[The mnemonic effects of benzodiazepines]. / Effets mnésiques des benzodiazépines.

The amnesiac effects of benzodiazepines were used soon after their introduction by anaesthetists for premedication. The aim was to crase any unpleasant memories of surgical intervention or its preparation. Unfortunately, these amnesiac effects are particularly undesirable in everyday living when the subject has to use his memory. The widespread usage of benzodiazepine anxiolytics for neurotic patients or depressives treated as out-patients, or treating sleeping problems, has led to a real problem of public health. Therefore, it is important to carry out trials with a strict methodology to understand the cognitive effects of these drugs, based on the application of the concepts and methods of the cognitive sciences (a field of rapid development in recent years). Whereas the amnesiac effects of benzodiazepines were ignored by physicians for years, their consequences are possibly overestimated at present, sometimes leading to a caricatural attitude in the usage of these products.