[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.

[Are catatonia and neuroleptic malignant syndrome related conditions?]. / Existe-t-il un lien entre catatonie et syndrome malin des neuroleptiques ?

INTRODUCTION: Catatonia and neuroleptic malignant syndrome are both conditions that can compromise survival and whose successful treatment depends on early diagnosis. OBJECTIVE: Distinguishing between these two conditions is difficult in a clinical setting and is further complicated by diagnostic criteria overlap. Are they both variations of a single disorder or two distinct conditions that happen to share certain characteristics? The goal of this paper is to review the available published data concerning the existence of a link between these two conditions and to specify the nature of the link between them. METHOD: We identified relevant articles from the PubMed registry by cross-referencing "catatonia" and "neuroleptic malignant syndrome". The articles returned were selected according to language (English and French) and publication date (before November 2007). RESULTS: Opinions are clearly divided concerning the existence of a link between these two conditions. The most commonly held opinion is that catatonia and neuroleptic malignant syndrome are two entities on the same spectrum. There are, however, no less than five different hypotheses concerning the nature of the link between them: first hypothesis: neuroleptic malignant syndrome is a drug-induced form of catatonia; second hypothesis: neuroleptic malignant syndrome is a drug-induced form of malignant catatonia; third hypothesis: neuroleptic malignant syndrome and malignant catatonia are one and the same; fourth hypothesis: catatonia is a risk factor for neuroleptic malignant syndrome; fifth hypothesis: neuroleptic malignant syndrome is a heterogeneous syndrome that includes both catatonic and non-catatonic responses to antipsychotic drugs. Other research maintains that catatonia and neuroleptic malignant syndrome are two distinct conditions. This point of view has fewer proponents, but benefits from historical, clinical and neurobiological studies that comfort this hypothesis. A careful clinical examination should in theory enable the distinction between these two entities and various neurobiological hypotheses are put forward to explain the differences between them. ANALYSIS AND DISCUSSION: The analysis of the data does not enable the elaboration of a single consensus on the existence of a link between catatonia and neuroleptic malignant syndrome. Additionally, the different hypotheses' level of scientific proof is insufficient to confirm or reject them. We only have at our disposal isolated case studies or studies with varying diagnostic criteria. CONCLUSION: A review of the literature does not enable us to confirm or invalidate a link between catatonia and neuroleptic malignant syndrome. However, answering this question would have direct consequences, since the suggestion of a link has led to the contraindication of neuroleptics for the treatment of catatonia, which contraindication has been extended on principle to the use of all newer antipsychotic medication. But since the link between catatonia and neuroleptic malignant syndrome has not been established according to scientific criteria, should the contraindication of atypical antipsychotic drugs be maintained in the treatment of catatonia?

[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.

[Clozapine-resistant schizophrenia related to an increased metabolism and benefit of fluvoxamine: four case reports]. / Inefficacité de la clozapine en rapport avec un métabolisme augmenté et intérêt de la fluvoxamine: à propos de quatre cas.

OBJECTIVE: Although clozapine currently remains the most effective option in treatment-resistant schizophrenia, approximately 40-70% of antipsychotic-resistant patients do not respond, or respond only partially, to clozapine. Because clozapine-resistant patients have limited alternative treatment options, in this study we propose a clozapine augmentation strategy with evidence-based support for some of them. BACKGROUND: Clozapine-resistance is often of metabolic origin. Clozapine is metabolized by N-oxidation and N-demethylation in the liver, predominantly by CYP450 1A2. Due to the influence of inhibitors, inducers, and genetic factors on CYP450 1A2-activity, there is extensive interindividual variability in clozapine plasma concentrations at a fixed dose. Consequently, monitoring of clozapine plasma concentrations is recommended. Several studies have suggested a significantly higher response rate at clozapine plasma concentration of less than 350 microg/l. Unfortunatly, some patients, especially young male smokers, do not achieve this minimum plasma concentration, even at doses higher than 900 mg/day and are nonresponders. CASE-REPORTS: We report the case of a 30 year-old smoker suffering from refractory schizophrenia, and responding poorly to treatments, including clozapine. Monitoring of the clozapine plasma concentration showed a very low level of clozapine, below the minimal effective dose of 350 microg/l. We initially suspected noncompliance with the treatment regime, but genetic analyses revealed another explanation: a gene polymorphism of the CYP450 1A2, principal enzyme that breaks down clozapine. The variability of CYP450 1A2 is explained by a gene polymorphism in intron 1. The A/A genotype confers high CYP450 1A2 inductivity in smokers. Certain smoking patients with A/A polymorphism have ultrarapid CYP450 1A2 activity, which causes the patient to metabolize clozapine too quickly. These patients do not respond to clozapine, even with doses higher than 900 mg/day. However, several factors can counter this elevated CYT activity, in particular fluvoxamine. The interaction between clozapine and fluvoxamine occurs via the inhibition of CYP450 1A2. Several studies have shown that administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5. Low doses of fluvoxamine inhibit the CYT activity, enough to raise the level of clozapine even when the dose of clozapine was reduced by 50%. The patient unfortunately developed a maniac episode during treatment with fluvoxamine, despite the absence of a previous history of bipolar illness, and we had to initiate treatment with lithium. Together, the three medications stabilized his condition satisfactorily for eight months. We describe three additional cases of treatment-refractory patients with schizophrenia and low-clozapine plasma levels despite high doses. They exhibited similar metabolic abnormality, as confirmed by a caffeine test, because plasma caffeine ratios reflect CYP450 1A2 activity. We then describe its correction, with low doses of fluvoxamine. These patients became responders when the plasma levels increased above the threshold. CONCLUSION: Consequently, we propose a therapeutic drug monitoring strategy. In the case of a clozapine-resistant schizophrenic patient, plasma clozapine levels should be tested. If the rate is normal, the resistance is not metabolic in origin. If the rate is low, a caffeine test should be done. If the results are normal, the patient is noncompliant with the treatment. If the caffeine test is abnormal, metabolic resistance is suspected. In such patients, we propose the addition of low-dose fluvoxamine while closely monitoring clozapine levels. Based on our experience, reducing the clozapine dose by 50% and prescribing 50 mg of fluvoxamine, so as to reach a minimum effective clozapine plasma concentration of more than 350 microg/l should provide an effective therapeutic strategy. This treatment may benefit the significant number of schizophrenic patients whose response to clozapine is hindered by metabolic hyper inductivity. Although this strategy may carry some risks for certain patients, the protocol we propose reduces the latter and the potential benefits should outweigh them.

Behavioral and psychological symptoms in Alzheimer's disease. Relation between apathy and regional cerebral perfusion.

Fundamental and therapeutic research in Alzheimer's disease (AD) focused for a long time exclusively on cognitive aspects. However, AD also frequently involves complex disorders of affect and behavior, which are currently grouped under the heading 'behavioral and psychological signs and symptoms of dementia' (BPSSD). Several rating tools have been developed over the years on the basis of a variety of source data. Some are derived from psychiatric practise or have specifically been developed for dementia, such as the Neuropsychiatric Inventory (NPI). In this study we prospectively used the NPI to examine BPSSD. Sixty-three French patients (mean age 74.7 years, SD 7.9) with a Mini-Mental State Examination (MMSE) score higher than 10 were examined. BPPSD were detected by NPI in 95. 2% of the patients. Anxiety was the most common abnormality (65.1%), followed by apathy and dysphoria (58.7%). The highest frequency x severity NPI score was observed for apathy. In order to identify the relationship between regional cerebral perfusion and apathy, 20 of these AD patients underwent a technetium-99m-bicisate SPECT protocol within the same week as the NPI evaluation. The mean age of this population was 74.4 years (SD 5.3) and the mean MMSE score was 21 (SD 4.1). The apathy NPI score was correlated with right cingulate deficit whereas the highest correlation for the MMSE was with the left temporoparietal area. This stresses the interest to focus on SPECT imaging of AD patients not only in the posterior areas. CopyrightCopyright 1999S.KargerAG,Basel

[Transsexualism]. / A propos du transsexualisme.

According to the literature, the transsexual phenomenon can be assessed as a distinct psychiatric illness. Transsexualism, a rare but spectacular disorder, realizes a gender identity reversal raising questions regarding systems of psychiatric diagnosis, nosology and treatment. A better clinical knowledge of this "experiment" and its follow-up allow studying processes contributory to marked deviation of gender identity and furthering concepts of development of masculinity and feminity. Current research deals with hypotheses that can be stated as testable propositions about underlying dynamics in various fields: learning factors, psychoanalytic components and psycho-biological data. Focusing on the early infantile development and the environmental influences reflects a variety of non specific psychogenetic precursors. The treatment of "gender dysphoria syndrom", i.e. hormonal treatment, sex-reassignment surgery and psychotherapic processes, aims towards réduction of psychic pain and social adjustment in the cross-gender role. Transsexual phenomenon largely overlaps the psychopathological area; beyond surgical and medical aspects, social implications and legal positions refer to an ethical problem.