[Sexual dysfunction and depression: Validity of a French version of the ASEX scale]. / Validation française de l'échelle psychométrique ASEX d'évaluation des troubles sexuels dans la dépression.

BACKGROUND: Since the Beck study (1967), it is well known that sexual dysfunction is particularly prevalent in depressive patients compared to the general population, at 70% and 30% respectively. Depression, psychotropics and antidepressants are responsible for altering sexuality, and patients are considerably affected by these symptoms that dramatically decrease their quality of life. Screening for sexual dysfunctions seems essential, and a scale such as the Arizona Sexual Experience Scale (ASEX) may help practitioners. The English version of this scale was validated in 2000 (McGahuey et al. [9]), and is widely used in scientific research. The aim of this study was to assess the validity of the French version of the ASEX scale. METHODS: Following authorization from the University of Arizona, the ASEX scale was translated into French by our team at the University hospital of Besançon (France), by the back translation technique, and then checked by a professional translator. ASEX, Mini International Neuropsychiatric Interview (MINI), Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) were filled out by 37 depressed inpatients, and ASEX and PHQ-9 by 64 controls (hospital employees, residents and students at the University of Besançon), and again one to two weeks later. Bivariate correlations were performed using total ASEX scores to determine the test-retest reliability. Internal consistency of the ASEX scale was assessed using Cronbach's alpha analysis. Analyses of variance (Anova) were performed to determine the validity of the ASEX scale to compare patients to controls for total ASEX score and for individual ASEX item scores. In order to determine whether the ASEX criteria accurately reflect sexual dysfunction (determined by the HDRS rating or self-report), positive and negative predictive value and sensitivity and specificity were measured. To determine how well the total ASEX score differentiates between individuals with sexual dysfunction and those without, a Receiver Operating Characteristic (ROC) analysis was performed. We expected similar results between the French version of the ASEX scale and the original one (McGahuey and al., 2000). RESULTS: Patients and controls were similar in terms of sex and age. The test-retest reliability was good, and the internal consistency was excellent using Cronbach's alpha analysis (alpha=0.9451). Analyses of variance (Anova) showed strong differences between the two groups, confirming the validity of the ASEX scale to compare patients to controls for total ASEX score and individual ASEX item scores. Positive and negative predictive values were respectively 89.66% (PPV) and 85.33% (NPV). Specificity and sensitivity were respectively 95.31% (Sp) and 70.27% (Se). The ROC analysis showed the area under the curve (AUC=0.8457) and the best ASEX criteria to demonstrate that sexual dysfunction had been correctly identified (total ASEX score ≥ 18). CONCLUSION: This study assessed the validity and reliability of the French version of the ASEX scale. These findings demonstrate the highly acceptable psychometric properties of ASEX in patients with depression.

[The therapeutic alliance in the initial stages of the management of depression by the general practitioner]. / L'alliance thérapeutique au début d'une prise en charge pour dépression par le généraliste.

In the field of depression, good initial management is crucial for the subsequent treatment. A relationship based on trust is essential. This can be of various types: there is no consensus on what is the "best" type of relationship. General practitioners diagnose more than two-thirds of depression and write out more than one third of prescriptions for antidepressors. Physicians are faced with various problems in the management of depressed patients: lack of time during the consultation, insufficient training in depression and its treatment, absence of somatic markers, fear of suicide risks... To specify the problems and elaborate responses, this survey assessed, mirror-wise, the point of view of the patient and that of the physician, the feelings regarding the pathology and its treatment, during consultations when the physician is confronted with a depression syndrome. Patient anonymousness was guaranteed by the use of a ballot box and sealed envelopes. In both parties, the survey explored the perception and experience of the pathology, the patient-physician relationship, and the history and perception of the initial consultations. Eligible patients were those who had been diagnosed with depression by the general practitioner and who had been informed of this during the past three months. Based on this information, and other than the data regarding the pathology, the procedure for establishing the diagnosis, the conditions in which the diagnosis was announced and the treatment measures, a characterisation of the alliance between the patient and the physician was established based on the combination of the patients' and physicians' data. Homogenous patient-physician groups were thus identified using multiple component factorial analysis followed by mixed classification. This methodology identified types of patient-physician binomials according to the nature of their alliance (independent of any "doctor effect"): a clinical alliance, a united alliance, an alliance based on sense, and a difficult alliance.

Pharmacogenetics and drug therapy in psychiatry--the role of the CYP2D6 polymorphism.

The importance of pharmacogenetics in medicine is growing with the identification of genetic variability by faster screening methods using automatic sequencers. A particularly interesting finding is that apart from environmental and psychological factors, drug response may be influenced by several biological factors as a result of genetic determinants leading to interindividual variability. Several mutations in genes coding for enzymes of the drug metabolizing system, as well as for neurotransmitter receptors or degrading enzymes and monoamine transport proteins, have been identified and investigated in psychiatry. But, despite the fact that some genetic polymorphisms of enzymes (mainly cytochrome P450 2D6) are well known, the application of pharmacogenetics as a therapeutic tool for improving patient care is rare. This review has three parts. In the first an overview is given of CYP450 characteristics and the genetic polymorphisms of interest to psychiatry. In the second the clinical implications of the CYP2D6 polymorphism are reviewed and in the third part other aspects on pharmacogenetic research in psychiatry are discussed. The aim of our review is to promote the application of pharmacogenetics in everyday clinical practice.

Validating affective temperaments in their subaffective and socially positive attributes: psychometric, clinical and familial data from a French national study.

BACKGROUND: One of the major objectives of the French National EPIDEP Study was to show the feasibility of systematic assessment of bipolar II (BP-II) disorder and beyond. In this report we focus on the utility of the affective temperament scales (ATS) in delineating this spectrum in its clinical as well as socially desirable expressions. METHODS: Forty-two psychiatrists working in 15 sites in four regions of France made semi-structured diagnoses based on DSM IV criteria in a sample of 452 consecutive major depressive episode (MDE) patients (from which bipolar I had been removed). At least 1 month after entry into the study (when the acute depressive phase had abated), they assessed affective temperaments by using a French version of the precursor of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS). Principal component analyses (PCA) were conducted on hyperthymic (HYP-T), depressive (DEP-T) and cyclothymic (CYC-T) temperament subscales as assessed by clinicians, and on a self-rated cyclothymic temperament (CYC-TSR). Scores on each of the temperament subscales were compared in unipolar (UP) major depressive disorder versus BP-II patients, and in the entire sample subdivided on the basis of family history of bipolarity. RESULTS: PCAs showed the presence of a global major factor for each clinician-rated subscale with respective eigenvalues of the correlation matrices as follows: 7.1 for HYP-T, 6.0 for DEP-T, and 4.7 for CYC-T. Likewise, on the self-rated CYC-TSR, the PCA revealed one global factor (with an eigenvalue of 6.6). Each of these factors represented a melange of both affect-laden and adaptive traits. The scores obtained on clinician and self-ratings of CYC-T were highly correlated (r=0.71). The scores of HYP-T and CYC-T were significantly higher in the BP-II group, and DEP-T in the UP group (P<0.001). Finally, CYC-T scores were significantly higher in patients with a family history of bipolarity. CONCLUSION: These data uphold the validity of the affective temperaments under investigation in terms of face, construct, clinical and family history validity. Despite uniformity of depressive severity at entry into the EPIDEP study, significant differences on ATS assessment were observed between UP and BP-II patients in this large national cohort. Self-rating of cyclothymia proved reliable. Adding the affective temperaments-in particular, the cyclothymic-to conventional assessment methods of depression, a more enriched portrait of mood disorders emerges. More provocatively, our data reveal socially positive traits in clinically recovering patients with mood disorders.

[Neuroleptic drug utilization among schizophrenic outpatients]. / Utilisation des neuroleptiques chez les patients ambulatoires souffrant de schizophrénie.

BACKGROUND: Our objective was to describe and compare neuroleptic drug utilization patterns among French schizophrenic outpatients in public and private care settings. METHODS: A cross sectional survey was carried out by a random sample of 61 public and 112 private psychiatrists who registered for one month all schizophrenic adult outpatients treated with a neuroleptic drug. Among registered patients, each psychiatrist was to include a maximum of 18 patients (public setting) or 9 patients (private setting). Statistical analysis was weighted to take into account for psychiatrist activity level, assessed by patient registration. RESULTS: Psychiatrists included 934 patients in the public care setting and 927 patients in the private care setting. Patients were (mean+/-sd) 40.1+/-12.1 years old, 60.9% men. The patients' social and clinical characteristics were less favorable in the public setting than in the private setting: no professional activity (78.9% vs 65.1%), living in institution (7.2% vs 3.7%), under legal protection (35.1% vs 14.5%), drug abuse (9.6% vs 5.6%). An atypical neuroleptic was prescribed for 63.0% of patients and a classic neuroleptic for 49.7%, an association of neuroleptics for 22.0%. In both settings, the most prescribed neuroleptics were olanzapine (28.0%) and risperidone (18.6%) with a higher mean daily dosage in the public care setting. At least one neuroleptic treatment change (drug and/or dosage) occurred during the previous year for 44.9% and 39.2% patients, in public and private settings, respectively. In both settings, reasons for changes were mainly lack of efficacy (55.1%) and side effects (49.8%). CONCLUSION: Public and private care populations were different but not as much as expected. In both settings, atypical neuroleptics were the predominant drugs used in the treatment of schizophrenia outpatients. The high frequency of drug change for lack of efficacy or side effects demonstrates the difficulties with the use of the present neuroleptic armamentarium.

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients.

Cytochrome P450-2D6 may be involved in the metabolism of many drugs such as psychotropic drugs and its genetic polymorphism is responsible for inter-individual differences in the therapeutic effect and toxicity of these drugs. Moreover with the same genetic basis, CYP2D6 metabolic capacity variations are observed. Different factors of variation may be involved, among them the prescribed drugs. The aim of this study was to compare the influence of two types of antidepressants, tricyclic (clomipramine) and serotonergic specific recapture inhibitor (SSRI) (fluoxetine), on the CYP2D6 metabolic capacity of depressed inpatients. The CYP2D6 phenotype (dextromethorphan test) was determined in 56 genotyped (PCR-SSCP) depressed caucasian inpatients with a heterozygous genotype. Forty-five subjects were treated with clomipramine and eleven received fluoxetine. The dextromethorphan metabolic ratio (MR) median was significantly higher in the fluoxetine group (0.255) than in the clomipramine group (0.083, p < 0.014). In this study, fluoxetine involved a greater decrease of CYP2D6 metabolic capacity than clomipramine. Clinical implications and the possible connection between a decreased CYP2D6 activity and adverse drug effects were discussed. Caution should be taken when drugs with a low therapeutic index must be coprescribed in such patients.

[Frequency and clinical aspects of bipolar II disorder in a French multicenter study: EPIDEP]. / Fréquence et aspects cliniques du trouble bipolaire II dans une étude multicentrique française: EPIDEP.

This paper presents the definite data from a French multi-center study (EPIDEP). The aim of EPIDEP was to show the feasibility of validating the spectrum of soft bipolar disorders by practicing clinicians. In this report we focus on data concerning the frequency of BP-II disorder and the key characteristics of BP-II by systematic comparison versus Unipolar depression. EPIDEP involved training 48 french psychiatrists in 15 sites; it is based on a common protocol following the DSM IV criteria (Semi-Structured Interview for Hypomania and Major Depression), and Akiskal (Soft Bipolarity), as well as criteria modified from the work of Angst (Hypomania Checklist), the Ahearn-Carroll Bipolarity Scale, HAM-D and Rosenthal Atypical Depression Scale; Semi-Structured Interview for Affective Temperaments (based on Akiskal-Mallya), self-rated Cyclothymia Scale (Akiskal). Comorbidity and family history (Research Diagnostic Criteria) were also obtained; EPIDEP was globally scheduled in two phases: Phase 1 devoted to recruiting major depressives, and phase 2 involved in more sophisticated assessment of soft bipolarity and administrating related measures. Results are presented on the total of 537 patients included at "visit 1" and 493 assessed for soft bipolarity at "visit 2". The BP-II global rate which was 21.7% at initial evaluation, nearly doubled (39.8%) by systematic evaluation of hypomania. Intergroup comparison versus unipolar depressives showed the following key characteristics of BP-II disorder: 1) distinct clinical presentation at index depressive episode despite uniformity in global intensity of depression (overrepresentation in BP-II of "suicidal thoughts", "guilt feelings", "depersonalisation-derealisation", "hypersomnia" "and weight gain"; and of "psychic anxiety" and "initial insomnia" in UP); 2) different course of illness with younger age of onset of first depression, higher rate of suicidal attempts, recurrency and hospitalisations; 3) more difficulties for recognition of the correct diagnosis; 4) more complex temperamental dysregulations (mixture of cyclothymic, hyperthymic and irritable traits which are highly represented in BP-II group); 5) higher rate in family history of mental disorders, especially bipolar disorders. Finally, EPIDEP data confirmed the diagnostic reliability of self-rating of hypomania and cyclothymia. With a systematic search of hypomania, almost 40% of major depressive episodes seen in psychiatric settings were classified as BP-II, of which only half were recognized by the clinicians at study inclusion. The BP-II validity as a distinct disorder from Unipolars was confirmed. Moreover, EPIDEP emphasized the reliability of self-rating in assessing soft-bipolarity (hypomania and cyclothymia). In total, EPIDEP data indicated that recognition of BP-II is feasible in diverse practice settings and proposed for clinicians some adapted clinical tools for assessing soft bipolarity.

Toward a refined phenomenology of mania: combining clinician-assessment and self-report in the French EPIMAN study.

BACKGROUND: Because manic patients lack insight, they are generally considered unreliable observers of their own psychopathology. The present analyses sought to examine to what extent patient reports could improve formal diagnostic criteria for mania--and be validated against the Carroll-Klein (CK) psychobiological model of bipolarity. METHOD: 104 DSM-IV acutely manic (hospitalized) patients provided self-assessment on the Ahearn--Carroll scale, the Multiple Visual Analogue Scales of Bipolarity (MVAS-BP). A principal component analysis (PCA) was performed on MVAS-BP, and the data on factorial scores were then compared to dimensional scores according to the CK model and to factors on the Beigel-Murphy Manic State Rating Scale (MSRS) completed by psychiatrists. RESULTS: The PCA identified a general factor accounting for 33% of the total variance; after varimax rotation, seven independent factors emerged, essentially in coherence with the signs and symptoms of DSM-IV mania, except for the 'social disinhibition' factor, which does not figure out as a distinct criterion in DSM-IV. Strong correlations were obtained (r > or = 0.80) between the four major factors of MVAS-BP and the four dimensional categories of the CK model: 'Consummatory Reward' with F1 'Elation and Inflated Self-esteem' (r=0.93), 'Incentive Reward' with F2 'Activation' (r=0.84), 'Psychomotor Pressure' with F3 'Acceleration' (r=0.85), and 'Central Pain' with F4 'Anxiety-Depression' (r=0.84). The F2 'Activation' appeared to be strongly correlated (r > or = 0.70) to all categories of the CK model. Correlational analysis between the factor structure of MVAS-BP and the MSRS showed significant coefficients on the scores assessing the emotional factors of 'Elation' and 'Depression.' Among the MVAS-BP factors, only 'Activation' was correlated to the majority of clinician ratings as obtained by the MSRS. CONCLUSIONS: These findings provide overall construct validity to the DSM-IV criteria for mania. Self-assessment of this disorder appears feasible and potentially useful in practice; lack of insight, poor judgment, and distractibility obviously require assessment by a clinician. Although our data are correlational and require prospective validation, they nonetheless suggest that (1) activation should be raised to the status of the stem criterion for mania, (2) to specify mood as elated, depressive, anxious, or irritable, and (3) to give individual status to social disinhibition (indiscriminate gregariousness) as a core pathological behavior in mania. Combining clinician- and self-observation thus produces a more precise and complete phenomenology of mania. We finally submit that the foregoing reformulation provides a psychobiological basis to the manic construct as formulated in the Carroll-Klein model.

The feasibility of self-assessment of dysphoric mania in the French national EPIMAN study.

BACKGROUND: There is presently considerable uncertainty on how to best assess mixed mania. The present contribution explores the feasibility of discriminating manic and dysphoric manic states on the basis of self-rating in the acute phase of the illness. METHODS: In the French four-site national EPIMAN study of 104 patients devoted to the clinical evaluation and subclassification of mania, we used the Multiple Visual Analog Scales of Bipolarity (MVAS-BP, 26 items) of Ahearn-Carroll in a self-assessment format. The study was conducted on consecutive patients hospitalized for an acute DSM-IV mania. The severity of mania was measured by the Beigel-Murphy scale (MSRS) assessed by psychiatrists. When mania abated, temperaments according to Akiskal and Mallya were administered in their French version. RESULTS: Principal component analysis revealed a general factor explaining 33% of the variance and, after rotation, seven factors defining different dimensions of the phenomenology of mania. The factorial scores, as well as the dimensional scores of the Carrol-Klein model significantly distinguished pure versus dysphoric mania made on clinical grounds. Gender seemed to influence two factors: high 'anxious-depressive' score in females (which is in line with female overrepresentation in mixed mania), vs. high score in males on the 'gregariousness' factor (which represents social disinhibition of the hyperthymic temperament known to be more prevalent in men). LIMITATION: Cross-sectional correlational study in need of longitudinal validation. CONCLUSIONS: EPIMAN data deriving from a national clinical population showed the feasiblity and face validity of self-assessment in acute mania, in particular its dysphoric subtype. Temperament in women seemed to contribute to the genesis of mixed (dysphoric) mania in accordance with Akiskal's hypothesis of opposition of temperament and polarity of bipolar episodes in mixed states. Self-assessment was capable of capturing accurately the subthreshold depressive symptomatology of mixed mania, which can be missed in hetero-evaluation by hasty clinical interview.

Population pharmacokinetics of clomipramine, desmethylclomipramine, and hydroxylated metabolites in patients with depression receiving chronic treatment: model evaluation.

Because metabolites play a major role in the clinical response to clomipramine, the objective of the current study was to develop a population model and evaluate its performance to describe the pharmacokinetic profiles of clomipramine (C) and its active metabolites desmethylclomipramine (DC), 8-hydroxy-clomipramine (OHC) and 8-hydroxy-desmethylclomipramine (OHDC). A first sample of 14 patients served for development of a 2-molecule C and DC model, which was shown to provide reasonable estimates of AUC-based clearances, as well as precise estimation of interindividual variability. Simulated data, generated to mimic a semi-rich sampling design and chronic treatment with clomipramine, indicated that clearance estimation was feasible under routine treatment conditions. A second sample of 30 patients, recruited prospectively and followed for a median 4-week period, was used to extend the 2-molecule model to a 4-molecule model. Goodness-of-fit assessment revealed that model-predicted concentrations were reasonably close to observed concentrations for a majority of patients. Interindividual variability was 50% to 60% for hydroxylation and desmethylation clearances, and residual variability was 30%. The proposed model incorporates much of what is known about the metabolism of clomipramine and may valuably integrate the influence of genetic and environmental factors on each metabolic pathway.

Drug extrapyramidal side-effects or not: is there a dextromethorphan phenotype difference?

A recent hypothesis suggests the possible role of cytochrome P450 2D6 (CYP2D6) polymorphism (involved in the metabolism of a large number of drugs), as a potential risk factor for the development of extrapyramidal side-effects of psychotropic drugs. The CYP2D6 metabolizer phenotype (dextromethorphan test) of 31 drug treated psychiatric adult patients suffering from extrapyramidal side-effects (group 1) and of 31 matched patients without drug side effects (group 2) were compared. In the first group, 13 poor metabolizer patients (41.9 per cent) were found, characterized by a dextromethorphan metabolic ratio > 0.3, and only two patients in the second group (6.4 per cent). These data provide some support for the notion that in subjects in whom CYP2D6 is probably saturated, the risk of drug extrapyramidal side-effects may be increased. In such patients the choice of psychotropic drugs 'without' this risk must be preferred.

[Extrapyramidal side effects of neuroleptic and antidepressant treatment: assessment of potential risk factors through CYP2D6 genetic polymorphism]. / Effets indésirables extrapyramidaux des neuroleptiques et antidépresseurs--recherche de facteurs de risque: rôle du polymorphisme génétique du CYP2D6.

The objective of this study was to assign metabolizer phenotype (cytochrome P450 2D6 or CYP2D6) to drug treated psychiatric adult patients to assess if the CYP2D6 polymorphism could be a potential risk factor for the development of extrapyramidal side effects of psychotropic drugs. Twenty-eight unrelated in-patients (16 men and 12 women) treated with antidepressants and/or antipsychotic drug were phenotyped using dextromethorphan. Two groups of patients were considered depending on the presence (n = 14) or not (n = 14) of extrapyramidal side effects. The mean dextromethorphan/dextrorphan metabolic ratio (log10) did not differ between the two groups of patients (-1.13 +/- 0.9 and -1.56 +/- 0.5, NS). But significantly more patients with extrapyramidal side effects (n = 4) than patients without side effects (n = 0) were poor metabolizers. This result could be due to a quantitative difference between the 2 groups of drug treatment cosegregated with dextromethorphan, but several authors reported that extrapyramidal side effects seemed not to be always related to high plasma drug levels. So the authors concluded that the 2D6 polymorphism could be a risk factor of poor neurologic tolerance of psychotropic drugs, but not only through pharmacokinetic consequences. CYP 2D6 is indeed expressed in brain and seems to interfer with the metabolism of dopamine and other related neurotransmitters.

Citalopram: an interaction study with clomipramine in a patient heterozygous for CYP2D6 genotype.

A pharmacokinetic interaction between the selective serotonin reuptake inhibitor citalopram and a tricyclic antidepressant, clomipramine, was noted in a patient treated for major depression and obsessive-compulsive disorder. After the addition of citalopram, a desmethylclomipramine plasma level increase and an 8-hydroacy-desmethylclomipramine plasma level decrease were observed. The CYP2D6 phenotype, determined when the patient received the antidepressant comedication, characterized a poor metabolizer status (dextromethorphan metabolic ratio >0.3), despite a heterozygous genotype containing a wild-type allele with extensive metabolic capacity and a mutant non-functional allele (CYP2D6*1A/CYP2D6*4A). This case seems to be one of the first descriptions of the clinical relevance of a CYP2D6 heterozygous genotype in a patient treated with antidepressant.