Drug metabolic enzyme genotype-phenotype discrepancy: High phenoconversion rate in patients treated with antidepressants.

Cytochromes from the P450 family (CYP) play a central role in the primary metabolism of frequently prescribed antidepressants, potentially affecting their efficacy and tolerance. There are however important differences in the drug metabolic capacities of each individual resulting from a combination of intrinsic and environmental factors. This variability can present an important risk for patients and increases the difficulty of drug prescription in clinical practice. Pharmacogenetic studies have uncovered a number of alleles defining the intrinsic metabolizer status, however, additional factors affecting cytochrome activity can modify this activity and result in a phenoconversion. The present study investigates the discrepancy between the genetically predicted and actually measured activities for the six most important liver cytochromes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) in a cohort of patients under antidepressant treatment, previously shown to have a high proportion of patients with low metabolizing activities. We now performed the genetic characterization of this cohort to determine the extent of the genetic versus environmental contribution in these decreased activities. For all enzyme tested, we observed an important rate of phenoconversion, affecting between 33 % and 65 % of the patients, as well as a significant (p < 1E-06) global reduction in the effective but not predicted activities of CYP2D6, CYP2C9 and CYP2C19 compared to the general population. Our results highlight the advantages of phenotyping versus genotyping as well as the increased risk of treatment failure or adverse effect occurrence in a polymedicated population.

Resting-state functional connectivity of emotion regulation networks in euthymic and non-euthymic bipolar disorder patients.

BACKGROUND: Previous functional magnetic resonance imaging studies in bipolar disorder (BD) have evidenced changes in functional connectivity (FC) in brain areas associated with emotion processing, but how these changes vary with mood state and specific clinical symptoms is not fully understood. METHODS: We investigated resting-state FC between a priori regions of interest (ROIs) from the default-mode network and key structures for emotion processing and regulation in 27 BD patients and 27 matched healthy controls. We further compared connectivity patterns in subgroups of 15 euthymic and 12 non-euthymic patients and tested for correlations of the connectivity strength with measures of mood, anxiety, and rumination tendency. No correction for multiple comparisons was applied given the small population sample and pre-defined target ROIs. RESULTS: Overall, regardless of mood state, BD patients exhibited increased FC of the left amygdala with left sgACC and PCC, relative to controls. In addition, non-euthymic BD patients showed distinctive decrease in FC between right amygdala and sgACC, whereas euthymic patients showed lower FC between PCC and sgACC. Euthymic patients also displayed increased FC between sgACC and right VLPFC. The sgACC-PCC and sgACC-left amygdala connections were modulated by rumination tendency in non-euthymic patients, whereas the sgACC-VLPFC connection was modulated by both the current mood and tendency to ruminate. CONCLUSION: Our results suggest that sgACC-amygdala coupling is critically affected during mood episodes, and that FC of sgACC play a pivotal role in mood normalization through its interactions with the VLPFC and PCC. However, these preliminary findings require replication with larger samples of patients.

Using admixture analysis to examine birth-cohort effects on age at onset of bipolar disorder.

OBJECTIVE: It is suggested that age at onset (AAO) of bipolar I disorder (BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis. METHOD: A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO × birth year distribution (n = 1865), we compared the best-fitting model for the observed AAO in patients born ≤1960 and >1960, (ii) to control for potential confounders, two separate subsamples born ≤1960 and >1960 were matched for age at interview (n = 250), and a further admixture analysis was undertaken. RESULTS: The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960. CONCLUSION: The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania.

Borderline personality disorder and childhood maltreatment: a genome-wide methylation analysis.

Early life adversity plays a critical role in the emergence of borderline personality disorder (BPD) and this could occur through epigenetic programming. In this perspective, we aimed to determine whether childhood maltreatment could durably modify epigenetic processes by the means of a whole-genome methylation scan of BPD subjects. Using the Illumina Infinium® HumanMethylation450 BeadChip, global methylation status of DNA extracted from peripheral blood leucocytes was correlated to the severity of childhood maltreatment in 96 BPD subjects suffering from a high level of child adversity and 93 subjects suffering from major depressive disorder (MDD) and reporting a low rate of child maltreatment. Several CpGs within or near the following genes (IL17RA, miR124-3, KCNQ2, EFNB1, OCA2, MFAP2, RPH3AL, WDR60, CST9L, EP400, A2ML1, NT5DC2, FAM163A and SPSB2) were found to be differently methylated, either in BPD compared with MDD or in relation to the severity of childhood maltreatment. A highly relevant biological result was observed for cg04927004 close to miR124-3 that was significantly associated with BPD and severity of childhood maltreatment. miR124-3 codes for a microRNA (miRNA) targeting several genes previously found to be associated with BPD such as NR3C1. Our results highlight the potentially important role played by miRNAs in the etiology of neuropsychiatric disorders such as BPD and the usefulness of using methylome-wide association studies to uncover such candidate genes. Moreover, they offer new understanding of the impact of maltreatments on biological processes leading to diseases and may ultimately result in the identification of relevant biomarkers.

Screening for bipolar disorder among outpatients with substance use disorders.

BACKGROUND: Comorbidity of bipolar disorder and alcohol or substance abuse/dependence is frequent and has marked negative consequences on the course of the illness and treatment compliance. The objective of this study was to compare the validity of two short instruments aimed at screening bipolar disorders among patients treated for substance use disorders. METHODS: The Mood Disorder Questionnaire (MDQ) and the Hypomania Checklist-32 (HCL-32) were tested with reference to the mood section of the Structured Clinical Interview for DSM-IV axis I disorders (SCID) in 152 patients, recruited in two outpatient clinics providing specialized treatment for alcohol and opiate dependence. RESULTS: According to the SCID, 33 patients (21.7%) had a diagnosis within the bipolar spectrum (two bipolar I, 21 bipolar II and 10 bipolar not otherwise specified). The HCL-32 was more sensitive (90.9% vs. 66.7%) and the MDQ more specific (38.7% vs. 77.3%) for the whole sample. The MDQ displayed higher sensitivity and specificity in patients treated for alcohol than for opiate dependence, whereas the HCL-32 was highly sensitive but poorly specific in both samples. Both instruments had a positive predictive value under 50%. CONCLUSIONS: Caution is needed when using the MDQ and HCL-32 in patients treated for substance use disorders.

[Hyperthymic and cyclothymic temperaments: attenuated forms of bipolar disorder?]. / Tempéraments hyperthymique et cyclothymique: expressions atténuées du trouble bipolaire?

A temperament is described as a temporally stable dimension, biologically determined. Several temperaments have been described (hyperthymic, depressive, cyclothymic, irritable and anxious) and could represent premorbid characteristics of an affective disorder. Some temperaments could thus correspond to chronic sub-affective states expressed as attenuated forms of mood disorder. Several studies suggest that a large proportion of bipolar patients have a hyperthymic or cyclothymic temperament. Moreover, temperaments seem to influence the clinical caracteristics of bipolar disorders. Future investigations will evaluate whether temperaments represent a predisposing factor, an attenuated form of bipolar disorders or a distinct entity.

[Bipolar disorder and attention deficit/hyperactivity disorder in adults: differential diagnosis or comorbidity]. / Trouble déficit d'attention-hyperactivité et trouble bipolaire chez l'adulte: diagnostic différentiel ou comorbidité?

Attention deficit/hyperactivity disorder (ADHD) can sometimes coexist with bipolar disorder (BD). Despite controversies about the coexistence of the two disorders, recent clinical as well as biological studies support the concept of comorbid adult ADHD and BD. Although there is some overlapping symptomatology between both disorders, ADHD can be diagnosed in patients suffering from with BD after a detailed clinical evaluation. Clinicians should be particularly attentive to specific symptoms in order to treat adequately both disorders since untreated ADHD comorbidity with BD is associated with poor clinical and socio-professional outcome.

Mindfulness-based cognitive therapy for bipolar disorder: a feasibility trial.

BACKGROUND: The present open study investigates the feasibility of Mindfulness-based cognitive therapy (MBCT) in groups solely composed of bipolar patients of various subtypes. MBCT has been mostly evaluated with remitted unipolar depressed patients and little is known about this treatment in bipolar disorder. METHODS: Bipolar outpatients (type I, II and NOS) were included and evaluated for depressive and hypomanic symptoms, as well as mindfulness skills before and after MBCT. Patients' expectations before the program, perceived benefit after completion and frequency of mindfulness practice were also recorded. RESULTS: Of 23 included patients, 15 attended at least four MBCT sessions. Most participants reported having durably, moderately to very much benefited from the program, although mindfulness practice decreased over time. Whereas no significant increase of mindfulness skills was detected during the trial, change of mindfulness skills was significantly associated with change of depressive symptoms between pre- and post-MBCT assessments. CONCLUSIONS: MBCT is feasible and well perceived among bipolar patients. Larger and randomized controlled studies are required to further evaluate its efficacy, in particular regarding depressive and (hypo)manic relapse prevention. The mediating role of mindfulness on clinical outcome needs further examination and efforts should be provided to enhance the persistence of meditation practice with time.

[Psychiatry]. / Psychiatrie.

Methods of brain stimulation such as transcranial magnetic stimulation, deep brain stimulation and vagus nerve stimulation may have a place in the treatment of depression or severe anxiety disorders resistant to conventional treatments. Several advances in chronotherapy as well as developments in treatment protocols have helped to prolong the antidepressant effect of sleep deprivation. The clinical applications of these methods in depressive episodes and especially in bipolar depression are discussed. The complete remission of a depressive episode and the maintenance of therapeutic benefit beyond the mere reduction of symptoms, have become important issues. The persistence of residual depressive symptoms is associated with increased risk of relapse: their recognition and treatment are illustrated in this article.

Self- and clinician-rated Montgomery-Asberg Depression Rating Scale: evaluation in clinical practice.

BACKGROUND: Time- and cost-effective self-rating scales of depressive symptoms are particularly valuable for frequent use in large-scale effectiveness trials. The aim of the present study was to examine the psychometric properties of the French version of the self-rated Montgomery-Asberg Depression Rating Scale (MADRS-S) and determine whether it might complement the MADRS in monitoring depression severity and change over time in routine clinical practice. METHODS: Sixty-three adult outpatients with a current depressive episode completed the MADRS-S and were interviewed with the MADRS on two occasions, within a 1-month interval. RESULTS: All patients readily accepted the MADRS-S. It showed good to excellent internal consistency (Cronbach's alpha 0.85 at Time 1; 0.94 at Time 2). Its factor structure revealed that a single component explained a large proportion of variability (47.0% at Time 1; 68.8% at Time 2). Concurrent validity of the self- and clinician-rated versions was good (Pearson's correlation coefficients for total scores 0.81 at Time 1; 0.91 at Time 2). The MADRS-S was sensitive to change over the 4-week observation period (correlation of 0.71 between change scores on self- and clinician-rated instruments). LIMITATIONS: Generalizability is restricted to outpatients with moderate to severe depression, and the MADRS-S ability to measure treatment effects needs to be examined. CONCLUSIONS: The present study indicates that the MADRS-S displays favourable psychometric properties and suggests that it might be a valid complement to the MADRS, both in research settings and clinical practice.

Self-rated residual symptoms do not predict 1-year recurrence of depression.

BACKGROUND: Residual depressive symptoms are generally documented as a risk factor for recurrence. In the absence of a specific instrument for the assessment of residual symptoms, a new 25-item Depression Residual Symptom Scale (DRSS) was elaborated and tested for recurrence prediction over a 1-year follow-up. SAMPLING AND METHODS: Fifty-nine patients in remission after a major depressive episode (MDE) were recruited in two centres. They were assessed with the DRSS and the Montgomery-Asberg Depression Rating Scale (MADRS) at inclusion and followed for 1 year according to a seminaturalistic design. The DRSS included specific depressive symptoms and subjective symptoms of vulnerability, lack of return to usual self and premorbid level of functioning. RESULTS: Severity of residual symptoms was not significantly associated with increased risk of recurrence. However, DRSS score was significantly higher among patients with three or more episodes than one to two episodes. Number of previous episodes and treatment interruption were not identified as significant predictors of recurrence. CONCLUSION: The proposed instrument is not predictive of depressive recurrence, but is sensitive to increased perception of vulnerability associated with consecutive episodes. Limitations include small sample size, seminaturalistic design (no standardisation of treatment) and content of the instrument.

Effects of ovariectomy in prepubertal goats.

The objectives of this study were to determine the effects of ovariectomy on mammary gland development in prepubertal goats and to validate this model to study mammogenesis in young dairy ruminants. In this experiment, 3 months of aged goats were ovariectomized (ovx) while shammed goats played as surgery controls (sham). Thereafter, sham and ovx goats were slaughtered at 7 months of age to provide tissue for the assays. Results demonstrated that proliferation of mammary of mammary epithelial cells was significantly lower in ovariectomized goats compared to control goats. In ovx animal, epithelium structures were completely overstretched and epithelial ducts were undeveloped with limited branching whereas control animals had classical complex arborescent units with multiple round ductules and limited stroma. Concerning ERalpha (estrogen receptor alpha), PR (progesterone receptor) and P450 (aromatase) expression, results showed number of ERalpha, PR and P450 positive cells was higher in shammed goats compared to ovariectomized goats. All this results suggested that goat mammogenesis and ovarian control are similar to prepubertal heifers and that young goats are a good model to study mammary gland development in ruminants. In conclusion, we demonstrated that ovariectomy of prepubertal goats decreased proliferation of mammary epithelial cells with a profound alteration of cell adhesion molecules.

[Screening for bipolar disorders: a review of the literature]. / Dépistage des troubles bipolaires: une revue de la littérature.

OBJECTIVE: The aim of this article is to review the major instruments proposed for screening for bipolar disorder among clinical or general, adult or paediatric populations. They were developed in order to improve the detection of this illness which, far too often, remains unrecognized. Several of these screening instruments are already translated into several languages and validated. METHODOLOGY: A systematic review of the literature published on this topic up to July 2007 was carried out, using the main electronic data base (Medline). The keywords employed included bipolar disorder, screening, questionnaire, diagnosis and early recognition. RESULTS: The studies reported here examine whether screening instruments perform similarly in various clinical and non-clinical samples. Different forms of the same questionnaire (like self-report or parent report used in paediatric samples) are sometimes compared, usually showing that parent reports supersede the adolescent self-report form. This is namely the case for the Mood Disorder Questionnaire (MDQ) which is a brief and widely tested tool, available both in adult and adolescent versions. The MDQ exhibits good psychometric properties in relation to sensitivity and specificity in adult psychiatric samples, but these are more limited in the general population. Moreover, it yields better sensitivity for BP type I than for other bipolar subtypes. This is also true for other screening instruments like the hypomania check list (HCL-32). In order to optimize the sensitivity for bipolar II disorders, proposals for changing the MDQ screening algorithm have been tested. DISCUSSION: Even though it does not replace a thorough clinical interview, the use of screening tools for bipolar disorder is widely advocated. We discuss the need for clinicians to rely upon instruments allowing for a rapid and economically feasible identification of this disorder. Involving family members in the evaluation process may also increase the rate of recognition. More studies are still required in order to improve diagnostic efficiency of the screening instruments.

Frequency of dysphoria and mixed states.

BACKGROUND: Mixed states are a complex entity in the field of mood disorders. Dysphoria has been advocated as an important clinical dimension of mixed states. The objective of this work is to study the frequency of dysphoria within a population of patients with DSM-IV major depressive and/or manic episodes and to determine if it may help establish diagnostic criteria for subthreshold cases of depressive or manic mixed states. SAMPLING AND METHODS: A total of 165 patients were assessed using the Mini International Neuropsychiatric Interview complemented by a section defining dysphoria as a constellation of 3 among 4 symptoms (inner tension, irritability, aggressive behavior and hostility). RESULTS: When classifying patients according to the number of symptoms of the opposite polarity, changes in the frequency of dysphoria revealed a clear contrast between the 2 opposite manic and depressive poles and the full mixed state (DSM-IV definition). The frequency of dysphoria was 17.5% in pure depression, 22.7% in pure mania and 73.3% in full mixed state. Two threshold effects were identified: (1) the frequency of dysphoria increased from 17.5 to 61.1% (p = 0.002) when the number of manic symptoms in DSM-IV depressed patients increased from 0 to 1, and (2) dysphoria increased from 14.3 to 69.2% (p = 0.057) when the number of depressive symptoms increased from 2 to 3 in DSM-IV manic patients. CONCLUSION: Dysphoria is strongly but not necessarily associated with mixed states. When used as a clinical marker for mixed states, dysphoria confirms the modern delimitations of sub-threshold mixed states by specifying the required number of symptoms of the opposite polarity (which could be lower for depressive mixed states than for manic mixed states). The study has limitations related to the inclusion of patients who are not drug-free, to the definition of dysphoria and to the sample size.

Bactericidal and virucidal activity of the alkalophilic P395D/L241V/T343A mutant of vanadium chloroperoxidase.

AIMS: Vanadium chloroperoxidase and its directed evolution mutant P395D/L241V/T343A were investigated for their antibacterial and antiviral potential at slightly alkaline pH and at a H(2)O(2) concentration that is low compared to current nonenzymatic formulations. METHODS AND RESULTS: Two bacteria (the Gram-negative Pseudomonas aeruginosa and the Gram-positive Staphylococcus aureus) and two viruses (the enveloped Herpes Simplex Virus and the nonenveloped Coxsackievirus B4) were incubated with the P395D/L241V/T343A mutant, 10 mmol l(-1) H(2)O(2) and 100 mmol l(-1) Br(-) at pH 8. Strong microbial reduction was observed and bactericidal and virucidal activities of the mutant were three to six orders of magnitude higher than for the wild-type enzyme. CONCLUSIONS: The P395D/L241V/T343A mutant of vanadium chloroperoxidase has a broad antimicrobial activity at alkaline conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: For many disinfection formulations, antimicrobial activity at slightly alkaline pH values is required. To date, only the wild-type vanadium chloroperoxidase has been studied for its antibacterial activity, and only at acidic to neutral pH values. Its antiviral activity (e.g. useful for the cleaning of medical equipment) was not studied before. The observed activity for the alkalophilic P395D/L241V/T343A mutant is an important step forward in the application of this robust enzyme as a component in disinfection formulations.

Phenomenology of mixed states: a principal component analysis study.

OBJECTIVES: To contribute to the definition of external and internal limits of mixed states and study the place of dysphoric symptoms in the psychopathology of mixed states. METHODS: One hundred and sixty-five inpatients with major mood episodes were diagnosed as presenting with either pure depression, mixed depression (depression plus at least three manic symptoms), full mixed state (full depression and full mania), mixed mania (mania plus at least three depressive symptoms) or pure mania, using an adapted version of the Mini International Neuropsychiatric Interview (DSM-IV version). They were evaluated using a 33-item inventory of depressive, manic and mixed affective signs and symptoms. RESULTS: Principal component analysis without rotation yielded three components that together explained 43.6% of the variance. The first component (24.3% of the variance) contrasted typical depressive symptoms with typical euphoric, manic symptoms. The second component, labeled 'dysphoria', (13.8%) had strong positive loadings for irritability, distressing sensitivity to light and noise, impulsivity and inner tension. The third component (5.5%) included symptoms of insomnia. Median scores for the first component significantly decreased from the pure depression group to the pure mania group. For the dysphoria component, scores were highest among patients with full mixed states and decreased towards both patients with pure depression and those with pure mania. CONCLUSIONS: Principal component analysis revealed that dysphoria represents an important dimension of mixed states.

The EACN scale for oil classification revisited thanks to fish diagrams.

The phase behavior of C(10)E(4)-oil-water systems at constant o/w ratio and variable temperature (fish diagram) has been investigated for several homologous oil families. The temperature T( *) and surfactant concentration C( *) at the critical point were determined for 10 n-alkanes varying from C(6) to C(28) as well as for a series of alkylcyclohexanes and alkylbenzenes. On the basis of T( *), equivalent alkane carbon numbers (EACN) were assigned to nonlinear alkanes, alkylbenzenes, and alkylcyclohexanes. The consistency of the method was shown by corroborating that the EACN values of oils previously investigated with other C(i)E(j) (dibutyl ether, squalane, isopropyl myristate, and dodecylbenzene) are the same when determined with C(10)E(4). The fact that two oils of different nature but with the same EACN (i.e., the same T( *)) do not exhibit the same C( *) is discussed in terms of monomeric solubility of the surfactant in the oil (CMC(oil)).

[Psychiatry]. / Psychiatrie.

Introduced this year on the Swiss market, duloxetine (Cymbalta) is a new antidepressant which inhibits the reuptake of noradrenaline and serotonin. Clinical studies have shown its efficacy in depression as well as in neuropathic pains (60-120 mg/day) with a good tolerability. In this paper are also included short reviews about the two large American studies developed by the National Institute of Mental Health in the fields of the treatment for depression (STAR-D) and of the antipsychotic treatments for schizophrenia (CATIE study). Its also reviews two questions of present interest: the use of the second generation antipsychotics for the treatment of bipolar depression and the concept of bipolar disorders in children.

A stepwise drug treatment algorithm to obtain complete remission in depression: a Geneva study.

QUESTIONS UNDER STUDY/PRINCIPLES: We describe the proportion of severely depressed outpatients reaching complete remission at the different stages of a drug treatment algorithm. We compare several treatment options for SSRI (selective serotonin reuptake inhibitor) non-responders and test the feasibility of the algorithm in clinical conditions. METHODS: Patients with severe depressive disorders (ICD-10; MADRS > or = 25) admitted to an academic outpatient clinic were enrolled in this algorithm-guided sequential treatment protocol (starting with an SSRI and ending with a tricyclic, lithium, triodothyronine combination). The general principle of the algorithm was to boost the drug therapy in the event of non-response. RESULTS: 135 patients entered the study and 131 were eligible for analysis. From this group, 86 patients dropped out (65.6%), 40 reached complete remission (30.5%) and 5 patients did not reach remission at all (3.8%). In the 117 patients to whom a last observation carried forward approach was applied, the median improvement of the MADRS score was 48.0% (range -20.7%-100%), with 48.7% of patients considered responders, 23.1% partial responders and 28.2% non-responders. Median retention time was 8 weeks (range 2-34). CONCLUSIONS: This algorithm-guided antidepressant treatment was acceptable for clinicians and resulted in an elevated final response rate among study completers. However, the dropout rate was high, mainly due to treatment interruption or non-observance.

Olanzapine plasma level in relation to antimanic effect in the acute therapy of manic states.

The aim of this study was to evaluate internal as well as external validity of the two most frequently used mania scales, the Young Mania Rating Scale (YMRS) and the Bech-Rafaelsen Mania Scale (MAS), in patients with DSM-IV mania. Mokken analysis was used to evaluate internal validity in which a coefficient of homogeneity of 0.40 or higher indicates that the total score is a sufficient statistic. The external validity was evaluated by plasma-level relationship of olanzapine. In total, 20 patients with DSM-IV mania were analysed, and the coefficient of homogeneity was acceptable for the MAS, but not for the YMRS. In a subgroup of females who over 2 weeks had received a fixed dose of 20 mg olanzapine daily, a significant association was found between MAS scores and plasma levels, but this association was not obtained with the YMRS. In conclusion, the MAS was found superior to the YMRS in regard to both internal and external validity.