Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental.

BACKGROUND: Clear guidance for successive antidepressant pharmacological treatments for non-responders in major depression is not well established. METHOD: Based on the RAND/UCLA Appropriateness Method, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of treatment-resistant depression. The expert guidelines combine scientific evidence and expert clinicians' opinions to produce recommendations for treatment-resistant depression. A written survey comprising 118 questions related to highly-detailed clinical presentations was completed on a risk-benefit scale ranging from 0 to 9 by 36 psychiatrist experts in the field of major depression and its treatments. Key-recommendations are provided by the scientific committee after data analysis and interpretation of the results of the survey. RESULTS: The scope of these guidelines encompasses the assessment of pharmacological resistance and situations at risk of resistance, as well as the pharmacological and psychological strategies in major depression. CONCLUSION: The expert consensus guidelines will contribute to facilitate treatment decisions for clinicians involved in the daily assessment and management of treatment-resistant depression across a number of common and complex clinical situations.

Clinical guidelines for the management of depression with specific comorbid psychiatric conditions French recommendations from experts (the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental).

BACKGROUND: Recommendations for pharmacological treatments of major depression with specific comorbid psychiatric conditions are lacking. METHOD: The French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of depression based on the RAND/UCLA Appropriatneness Method. Recommendations for lines of treatment are provided by the scientific committee after data analysis and interpretation of the results of a survey of 36 psychiatrist experts in the field of major depression and its treatments. RESULTS: The expert guidelines combine scientific evidence and expert clinician's opinion to produce recommendations for major depression with comorbid anxiety disorders, personality disorders or substance use disorders and in geriatric depression. CONCLUSION: These guidelines provide direction addressing common clinical dilemmas that arise in the pharmacologic treatment of major depression with comorbid psychiatric conditions.

[French Society for Biological Psychiatry and Neuropsychopharmacology and Fondation FondaMental task force: Formal Consensus for the management of treatment-resistant depression]. / Prise en charge des troubles dépressifs résistants : recommandations françaises formalisées par des experts de l'AFPBN et de la fondation FondaMental.

Major depression represents among the most frequent psychiatric disorders in the general population with an estimated lifetime prevalence of 16-17%. It is characterized by high levels of comorbidities with other psychiatric conditions or somatic diseases as well as a recurrent or chronic course in 50 to 80% of the cases leading to negative repercussions on the daily functioning, with an impaired quality of life, and to severe direct/indirect costs. Large cohort studies have supported that failure of a first-line antidepressant treatment is observed in more than 60% of patients. In this case, several treatment strategies have been proposed by classical evidence-based guidelines from internationally recognized scientific societies, referring primarily on: I) the switch to another antidepressant of the same or different class; II) the combination with another antidepressant of complementary pharmacological profile; III) the addition of a wide range of pharmacological agents intending to potentiate the therapeutic effects of the ongoing antidepressant medication; IV) the association with appropriate psychological therapies; and, V) the use of non-invasive brain stimulation techniques. However, although based on the most recently available data and rigorous methodology, standard guidelines have the significant disadvantage of not covering a large variety of clinical conditions, while currently observed in everyday clinical practice. From these considerations, formalized recommendations by a large panel of French experts in the management of depressed patients have been developed under the shared sponsorship of the French Association of Biological Psychiatry and Neuropsychopharmacology (AFPBN) and the Fondation FondaMental. These French recommendations are presented in this special issue in order to provide relevant information about the treatment choices to make, depending particularly on the clinical response to previous treatment lines or the complexity of clinical situations (clinical features, specific populations, psychiatric comorbidities, etc.). Thus, the present approach will be especially helpful for the clinicians enabling to substantially facilitate and guide their clinical decision when confronted to difficult-to-treat forms of major depression in the daily clinical practice. This will be expected to significantly improve the poor prognosis of the treatment-resistant depression thereby lowering the clinical, functional and costly impact owing directly to the disease.

[French Society for Biological Psychiatry and Neuropsychopharmacology task force. Formal consensus for the treatment of bipolar disorder: an update (2014)]. / Recommandations Formalisées d'Experts de l'Association Française de Psychiatrie Biologique et Neuropsychopharmacologie sur le dépistage et prise en charge du trouble bipolaire : mise à jour 2014.

As part of a process to improve the quality of care, the French Society for Biological Psychiatry and Neuropsychopharmacology developed in 2010 formal consensus guidelines for the treatment of bipolar disorder. The evolution of therapeutic options available in France for the treatment of bipolar disorder has justified the update of this guideline. The purpose of this work was to provide an updated and ergonomic document to promote its use by clinicians. This update focuses on two of the six thematic previously published (acute treatment and long-term treatment). Aspects of the treatment of bipolar patients sparking debate and questions of clinicians (use of antidepressant, place of the bitherapy, interest of long-acting antipsychotics…) were also covered. Finally, we proposed graded recommendations taking into account specifically the risk-benefit balance of each molecule.

[Evaluation of functional remission in schizophrenic disorder. The FROGS Scale]. / Évaluation de la rémission fonctionnelle dans le trouble schizophrénique: l'échelle FROGS.

INTRODUCTION: Functional remission is an important treatment goal in schizophrenia, as independent living and reintegration of patients into the community is the ultimate goal of any treatment. Nevertheless, assessing functional remission in schizophrenia is problematic, as it is a multifactorial entity reflecting various aspects such as symptoms severity, personal skills and sociocultural expectancies. METHOD: The purpose of this study was to create and validate a novel scale for the evaluation of functional remission in schizophrenia. Unlike previous scales, this one was built on the basis of patients with few schizophrenia symptoms. The "Functional Remission of General Schizophrenia" (FROGS) scale was developed using the expert consensus method following a MEDLINE and standard database search. Out of the 61 initially proposed, 19 items were selected as gathering the core aspects of functional remission in schizophrenia detected in the literature. The FROGS was then evaluated in 432 patients with DSM-IV criteria of schizophrenia, all of them meeting Andreasen's symptomatic remission criteria. Such an instrument should have a stable structure over time but also be able to detect improvement in functioning with time. So we have further analysed the validity of the FROGS scale, specifically assessing time stability. We re-evaluated the initial patient sample around 1.5 years after the first evaluation (mean=17.1 months ± 1.9), restricting the analyses to patients who were still being followed-up and in clinical remission (n=140). RESULTS: Total score was highly reliable. Exploratory factor analysis after oblique rotation revealed that a three-factor solution was the most meaningful. On the basis of item content these three factors were labelled 'Social Functioning', 'Daily Life' and 'Treatment'. The FROGS total score can be used to measure a general construct for the evaluation of functional remission in schizophrenia. The mean FROGS total score was 75.8 (sd=10.8) at the second evaluation showing a significant improvement with time (3.8; P<0.0001 versus the first evaluation). The internal consistency/reliability of the FROGS scale was still very high (Cronbach's α=0.919). Significant improvement between the first and second evaluation were also apparent for all the individual items in the FROGS scale (P<0.01) as well as for the subscores for three extracted factors (P<0.0001). Statistically significant correlations were observed between the FROGS scale and other indices, including the Global Assessment of functioning (r=0.58; P<0.0001). These results provide further evidence of the solid psychometric properties of the FROGS scale. DISCUSSION/CONCLUSION: The results of these two validation studies provide further evidence of the scale's utility and its solid psychometric properties. Furthermore, it is sensitive to the duration of clinical remission. Our scale may be a step towards developing a consensual definition of functional remission in schizophrenia.

[French Society for Biological Psychiatry and Neuropsychopharmacology task force: Formal Consensus for the prescription of depot antipsychotics]. / Recommandations Formalisées d'Experts de l'AFPBN : prescription des neuroleptiques et antipsychotiques d'action prolongée.

BACKGROUND: Compliance is often partial with oral antipsychotics and underestimated for patients with serious mental illness. Despite their demonstrated advantages in terms of relapse prevention, depot formulations are still poorly used in routine. As part of a process to improve the quality of care, French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) Task Force elaborated a Formal Consensus for the prescription of depot antipsychotics in clinical practice. METHODS: The Task Force recommends as first-line choice, the use of long-acting injectable (LAI) second-generation antipsychotics in patients with schizophrenia, schizoaffective disorder and delusional disorder. They can be considered as a second-line option as a monotherapy to prevent manic recurrence or in combination with mood stabilizer to prevent depressive recurrence in the maintenance treatment of bipolar disorder. LAI second-generation antipsychotics can also be used after a first episode of schizophrenia. Depot neuroleptics are not recommended during the early course of schizophrenia and are not appropriate in bipolar disorder. They are considered as a second-line option for maintenance treatment in schizophrenia. RESULTS: LAI formulations should be systematically proposed to any patients for whom maintenance antipsychotic treatment is indicated. LAI antipsychotics can be used preferentially for non-compliant patients with frequent relapses or aggressive behaviors. CONCLUSION: A specific information concerning the advantages and inconveniences of the LAI formulations, in the framework of shared-decision making must be delivered to each patient. Recommendations for switching from one oral/LAI form to another LAI and for using LAI antipsychotics in specific populations (pregnant women, elderly patients, subjects in a precarious situation, and subjects having to be treated in a prison establishment) are also proposed.

[New medical device hospital assessment: what kind of clinical data?]. / Évaluation des DM innovants au sein des hôpitaux : avec quelles données cliniques ?

INTRODUCTION: Since 2003, the AP-HP medical devices committee (CODIMS) assess the therapeutic relevance of innovated medical device (MD) for the French AP-HP hospitals' group. To accomplish this task, the CODIMS asks manufacturers to bring out clinical arguments to justify the use of their MD in hospital. This work analyses retrospectively after 8years, all assessed MD until March 2011 and the scientific quality of the clinical data submitted by manufacturers to the CODIMS to purchase their MD. METHOD: All MD were classed according to their certification's level (I, IIa, IIb, III, DMIA). The quality of available clinical studies (CS) provided by manufacturers for each case was assessed and classed according to five clinical relevance levels based on the evidence-based medecine standards (1-2: high methodology; 3-5: low methodology). RESULTS: One hundred and three MD files (80 % of class IIb and III MD) were analysed by the CODIMS (630CS). Our results highlight the lack of relevance of files that are provided to assess innovated MD: 29 files without any CS; concerning class IIb (32DMS, 221CS) and III (50, 342CS) MD, only 6 % of CS presented a correct clinical relevance level. And the situation did not get better during this assessment period. DISCUSSION/CONCLUSION: The CODIMS deplore the poor clinical relevance of files provided to assess MD (wrong comparator, inappropriate ends-points, insufficient follow-up to assess long-term security, small population studied). Future legislative developments for MD assessment are expected to improve this situation.

Breast-conserving surgery with or without radiotherapy vs mastectomy for ductal carcinoma in situ: French Survey experience.

From March 2003 to April 2004, 77 physicians throughout France prospectively recruited 1289 ductal carcinoma in situ (DCIS) patients and collected data on diagnosis, patient and tumour characteristics, and treatments. Median age was 56 years (range, 30-84). Ductal carcinoma in situ was diagnosed by mammography in 87.6% of patients. Mastectomy, conservative surgery alone (CS) and CS with radiotherapy (CS+RT) were performed in 30.5, 7.8 and 61.7% of patients, respectively. Thus, 89% of patients treated by CS received adjuvant RT. Sentinel node biopsy (SNB) and axillary dissection (AD) were performed in 21.3 and 10.4% of patients, respectively. Hormone therapy was administered to 13.4% of the patients (80% tamoxifen). Median tumour size was 14.5 mm (6, 11 and 35 mm for CS, CS+RT and mastectomy, respectively, P<0.0001). Nuclear grade was high in 21% of patients, intermediate in 38.5% and low in 40.5%. Excision was considered complete in 92% (CS) and 88.3% (CS+RT) of patients. Oestrogen receptors were positive in 69.8% of assessed cases (31%). Treatment modalities varied widely according to region: mastectomy rate, 20-37%; adjuvant RT, 84-96%; hormone treatment, 6-34%. Our survey on current DCIS management in France has highlighted correlations between pathological features (tumour size, margin and grade) and treatment options, with several similar variations to those observed in recent UK and US studies.

Validation of a four items version of the Functional Remission of General Schizophrenia scale (the mini-FROGS) to capture the functional benefits of clinical remission.

OBJECTIVES: We previously developed the Functional Remission Of General Schizophrenia (FROGS) scale demonstrating first, reliable assessment in a cross-sectional study and second, good time-stability. The purpose of the present analysis was to propose a shorter version (mini-FROGS), more compatible with the limited time available in a psychiatric visit, focusing on the functional domains that have higher likelihood of being improved with higher and/or longer symptomatic remission in different cultural backgrounds. METHODS: We used multiple regressions to find the most informative items explaining increased length of symptomatic remission, using prospective data from a national observational multicenter survey. Then, the mini-FROGS was used in different European countries to test its between-center reliability, compared to other scales. RESULTS: Four domains were retained as capturing the maximum of symptomatic remission, namely (1) travel and communication, (2) management of illness and treatment, (3) self-esteem and sense of independence and (4) respect of biological rhythms. First, the mini-FROG was evaluated in 443 French patients with clinical remission and 22 without, and 12/18 months later in 140 patients still in clinical remission and 23 in relapse. In Europe, 295 schizophrenia patients were assessed with the mini-FROGS and other scales devoted to functional remission, allowing comparisons. The mini-FROGS showed good correlations with other scales in different countries and demonstrated good psychometric properties. CONCLUSION: These results give evidence that a 4 items-only version of the FROGS scale may be useful to assess important aspects of functional remission, tightly linked to the length of clinical remission.

Hypovitaminosis D and Its Associated Factors in North Algerian Postmenopausal Women: Results of a Cross-Sectional Study.

PURPOSE: As the vitamin D status of Algerian postmenopausal women was poorly described, this cross-sectional study investigated the prevalence of low vitamin D status in a sample population. Secondarily, predictive factors of this hypovitaminosis D were explored. METHODS: All the 336 selected women ≥ 45 years from Douera were interviewed to get anthropometric and lifestyle data, reproductive and medical history, medications, and calcium/vitamin D intakes. A blood sample was collected to measure 25-hydroxyvitamin D (25(OH)D) concentrations. RESULTS: Approximately 86% of subjects had low vitamin D status (<20 ng/mL). Mean 25(OH)D level was 14.4 ± 5.3 ng/mL with a clear seasonal dynamic and a significant negative correlation with PTH levels (r = -0.15, p=0.006). A multiple regression analysis using the 25(OH)D cutoff value of 17 ng/mL instead of the generally admitted level of 20 ng/mL was performed to increase statistical power. Other seasons than summer (OR 4.159 and 95% CI 2.456-7.043), obesity (≥30 kg/m2, OR 1.826, 95% CI 1.081-3.083), and veiling (OR 3.526, 95% CI 1.090-11.400) were significantly associated with 25(OH)D concentrations <17 ng/mL. CONCLUSIONS: In North Algeria, the abundant sunlight appears insufficient to fully offset hypovitaminosis D risk factors in postmenopausal women, especially obesity and veiling. It suggests the major need to increase vitamin D supplementation in this subpopulation.

Validating the soft bipolar spectrum in the French National EPIDEP Study: the prominence of BP-II 1/2.

BACKGROUND: Much of the current literature on bipolar disorder is focused on bipolar I (BP-I), and to a much lesser extent on bipolar II (BP-II). The French multi-center national EPIDEP study has, among its objectives, the feasibility of validating a broader spectrum of bipolarity (the so-called "soft spectrum") by practicing clinicians. In this report we test aspects of a bipolar schema proposed earlier by Akiskal and Pinto [Akiskal, H.S., Pinto, O., 1999. The evolving bipolar spectrum: Prototypes I, II, III, IV. Psychiatr. Clin. North Am. 22: 517-534.]. METHODS: EPIDEP was scheduled in three phases: Phase 1 to recruit DSM-IV major depressives; Phase 2 to assess hypomania and affective temperaments; and Phase 3 to obtain history on course of illness, family history, and comorbidity. Comparative analyses are presented between affective subgroups constructed on a hierarchical basis: spontaneous hypomania (BP-II), cyclothymic temperament (BP-II 1/2), antidepressant-associated hypomania (BP-III), hyperthymic temperament (BP-IV), versus "strict unipolar" (UP). RESULTS: We present data on 490 patients for whom we obtained full assessment during all three phases of the study, classified as BP-II 1/2 (N=164), II (N=61), III (N=28), IV (N=22), as well as UP (N=174) as the reference nonbipolar group. Systematic inter-group comparison among the soft spectrum showed significant differences along clinical, descriptive, course, pharmacologic response and familial affective disorder patterns, which confirm the heterogeneity of the soft bipolar spectrum, with special characteristics for each of the subgroups. In terms of external validation, familial bipolar loading characterized all soft bipolar subgroups except type IV. LIMITATION: Data collection conducted in a practice setting, clinicians cannot be entirely held "blind" to all measures. This is an exploratory attempt, with many variables examined, to help characterize the clinical terrain of soft bipolarity. CONCLUSION: This is nonetheless the first systematic clinical attempt to validate the bipolar spectrum beyond mania (BP-I). BP-II 1/2, BP-III and BP-IV appeared distinct from BP-II and strict UP -- along most of the variables examined. BP-II 1/2 -- with early onset complex temperament structure, and high mood instability, rapid switching, irritable ("dark") hypomania and suicidality -- emerged as the most prevalent and severe expression of the bipolar spectrum, and accounting for 33% of all MDE. These results, which are of great public health relevance, testify to the cyclic nature of bipolarity in its softest expressions. The soft phenotypes are also of interest for genetic investigations of bipolar disorder.

Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients.

BACKGROUND: Despite extensive research recently focused on mixed mania, it is uncertain as how best to define it clinically, psychometrically (which has major bearing on its prevalence), and the methodology needed for future research. This topic is also of historical interest, because Magnan (1890) [Magnan, V., 1890. La Folie Intermittente. G Masson, Paris.] suggested that "combined [mixed] states" linked Falret's "circular insanity" with Baillarger's "dual insanity" (both described in 1854). This work eventually led to the Kraepelinian synthesis of all manic, mixed, and depressive states into the unitary rubric of "manic-depressive insanity (1899/1921). METHOD: EPIMAN-II Thousand" (EPIMAN-II MILLE) is a French national collaborative study, which involved training 317 psychiatrists working in different sites representative of psychiatric practice in France. We recruited 1090 patients hospitalized for acute DSM-IV mania. assessed at index admission by the following measures: the Mania Rating Scale (MRS), the Beigel-Murphy Scale (MSRS), a newly derived checklist of depressive symptoms least contaminated by mania, MADRS for severity of depression, and the SAPS for psychotic features. RESULTS: The rate of mixed mania, as defined by at least 2 depressive symptoms, was 30%. Even with this broad definition, we found significantly higher female representation. This clinical sub-type of mania was characterized by high frequency of past diagnostic errors, particularly those of anxiety and personality disorders. Refined definition of co-exiting depression was obtained from an abbreviated version of the MADRS (6 items), with distinct "emotional-cognitive" symptoms, and "psychomotor inhibition" factors, both of which were separable from an "irritable" factor linked to lability and poor judgment. Mixed mania was psychometrically best identified by a MADRS score of 6 (80% sensitivity, 94% specificity) and validated by a mixed polarity of first episodes, a higher rate of recurrence, psychotic features, and suicide attempts. LIMITATION: Cross-sectional study. CONCLUSIONS: The data deriving from EPIMAN, the largest and only national study ever conducted on mania, provide definitive characterization of the clinical and psychotic structure of mixed mania, which accounts for 1 out of 3 patients who present with mania. This figure is more accurate than higher rates reported in the literature because, in describing "mixity", we eliminated depressive features that could be contaminated by mania. Despite the prominent affective features described herein, the bipolar nature of mixed mania is often missed, with the result that these patients are diagnosed as having anxiety and/or personality disorders. It is of great public health significance for psychiatrists to recognize the bipolar nature of this condition that has been known as a major phase of manic-depressive illness since at least Magnan, a disciple of Falret and Baillarger.

Mood stabilizer augmentation in apparently "unipolar" MDD: predictors of response in the naturalistic French national EPIDEP study.

BACKGROUND: Mood stabilizers (MS), especially Lithium, are used in augmentation strategies for resistant depression. However the broader bipolar spectrum (depressions with brief [i.e. 2 days] hypomania, cyclothymic and hyperthymic temperaments) has rarely been explored in such strategies. The aim of the current report is to search for predictive factors for response to mood stabilizers when used as augmentation therapy after excluding clear-cut hypomania and focusing on DSM-IV major depressive disorder (UP-MDD), which is best designated as apparently "unipolar". METHOD: From the total sample of 452 major depressives (MDE) included in the French National study EPIDEP, 256 were classified as UP-MDD after eliminating DSM-IV bipolar II (> or =4 days of hypomania); conservatively, we also excluded MDD with hypomania associated with antidepressants. Lifetime treatment history of UP-MDD revealed that 59 (23.3%) had received at least one MS (lithium, valpromide [French variant of divalproex], and carbamazepine) in the past; from this sub-population, 18 were considered retrospectively as good responders (30%, GR) versus 41 poor responders (70%, PR) to MS augmentation on the basis of the clinical judgment of the treating psychiatrist. RESULTS: Comparative analyses between patients who received MS and those who did not, revealed the former group as having higher levels on the hypomania checklist and cyclothymic and depressive temperaments. The delay to MS installation was significantly longer in the PR versus GR. The profile of GR could be described as follows: younger current age, higher education; symptom-free interval between major episodes; and fewer prior depressive episodes and hospitalizations; and higher rate of MS prescription. However, no significant differences were obtained from hypomania assessment and affective temperament ratings (cyclothymic, hyperthymic, depressive). During the index (most recent) depressive episode, we obtained a significantly higher rating of "suicidal thoughts" associated with higher levels of "sadness-guilt," psychomotor agitation, and lower "retardation-fatigue" (all from the HAM-D) in the PR group; better and faster response to current treatment (as prospectively assessed) were also observed in the GR. At this time, overall severity of depression was not linked to the quality of response to the MS. LIMITATIONS AND CONCLUSION: Despite its retrospective design, these analyses have important implications in the management of difficult or resistant "unipolar" depression by using MSs as augmentation strategy. Clinicians appeared to have used "subtle" hypomanic and cyclothymic features as a justification for augmentation. However, these features per se were not predictive of response to such augmentation. Instead, the profile of augmentation response to failed antidepressants appears to be an "activated depression" (significantly less retardation and withdrawal and higher agitation associated with greater intensity of painful and guilt-ridden sadness with suicidality), and the significantly higher rate of and earlier prescription of MSs in the course of recurrent MDD. These data suggest that resistant depressives should not stay on antidepressant or antidepressant combination for too long; MS augmentation must be instituted without much delay.

Cyclothymic temperament as a prospective predictor of bipolarity and suicidality in children and adolescents with major depressive disorder.

INTRODUCTION: Although several recent studies suggest that bipolar disorder most commonly begins during childhood or adolescence, the illness still remains under-recognized and under-diagnosed in this age group. As part of the French Bipolar network and in line with the hypothesis that juvenile depression is pre-bipolar , we evaluated the rate of onset of bipolar disorders in a naturalistic 2-year prospective study of consecutive, clinically depressed children and adolescents, and to test whether the cyclothymic temperament underlies such onset. METHODS: Complete information was obtained from both parents and patients in 80 of 109 depressed children and adolescents assessed with Kiddie-SADS semi-structured interview, according to DSM IV criteria. They were also assessed with a new questionnaire on cyclothymic-hypersensitive temperament (CHT) from the TEMPS-A cyclothymic scale adapted for children (provided in ), and other assessment tools including the Child Depression Inventory (CDI), Young Mania Rating Scale, Clinical Global Assessment Scale (CGAS), and Overt Aggressive Scale (OAS). RESULTS: Of the 80 subjects, 35 (43%) could be diagnosed as bipolar at the end of the prospective follow-up. This outcome was significantly more common in those with cyclothymic temperament measured at baseline. Most of these patients were suffering from a special form of bipolar disorder, characterized by rapid mood shifts with associated conduct disorders (CD), aggressiveness, psychotic symptoms and suicidality. LIMITATION: The primary investigator, who took care of the patients clinically, was not blind to the clinical and psychometric data collected. Since all information was collected in a systematic fashion, the likelihood of biasing the results was minimal. CONCLUSION: We submit that the CHT in depressed children and adolescents heralds bipolar transformation. Unlike hypomanic or manic symptoms, which are often difficult to establish in young patients examined in cross-section or by history, cyclothymic traits are detectable in childhood. Our data underscore the need for greater effort to standardize the diagnosis and treatment of pre-bipolar depressions in juvenile patients.

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.

Diflunisal versus placebo for treatment of pain in general practice.

The efficacy and safety of diflunisal versus placebo in the treatment of pain were compared in a multicenter, double-blind study of 1,037 patients treated for seven days by general practitioners. A statistically significant (P less than 0.001) difference in favor of diflunisal was seen using four evaLuation criteria. The incidence of side effects was generally low with both treatments; nevertheless, the number of patients suffering at least one side effect was greater after diflunisal than after placebo (P less than 0.05). A comparison of the profile of responders to diflunisal and to placebo showed no particular pattern.

Cyclothymic OCD: a distinct form?

BACKGROUND: Clinical research on the comorbidity of obsessive compulsive disorder (OCD) and other anxiety disorders has largely focused on depression. However in practice, resistant or severe OCD patients not infrequently suffer from a masked or hidden comorbid bipolar disorder. METHOD: The rate of bipolar comorbidity in OCD was systematically explored among 453 members of the French Association of patients suffering from OCD (AFTOC) as well as a psychiatric sample of OCD out-patients (n=175). As previous research by us has shown the epidemiologic and clinical sample to be similar, we combined them in the present analyses (n=628). To assess mood disorder comorbidity, we used structured self-rated questionnaires for major depression, hypomania and mania (DSM-IV criteria), self-rated Angst's checklist of Hypomania and that for the Cyclothymic Temperament (French version developed by Akiskal and Hantouche). RESULTS: According to DSM-IV definitions of hypomania/mania, 11% of the total combined sample was classified as bipolar (3% BP-I and 8% BP-II). When dimensionally rated, 30% obtained a cut-off score >/=10 on the Hypomania checklist and 50% were classified as cyclothymic. Comparative analyses were conducted between OCD with (n=302) versus without cyclothymia (n=272). In contrast to non-cyclothymics, the cyclothymic OCD patients were characterized by more severe OCD syndromes (higher frequencies of aggressive, impulsive, religious and sexual obsessions, compulsions of control, hoarding, repetition); more episodic course; greater rates of manic/hypomanic and major depressive episodes (with higher intensity and recurrence) associated with higher rates of suicide attempts and psychiatric admissions; and finally, a less favorable response to anti-OCD antidepressants and elevated rate of mood switching with aggressive behavior. LIMITATION: Hypomania and cyclothymia were not confirmed by diagnostic interview by a clinician. CONCLUSION: Our data extend previous research on "OCD-bipolar comorbidity" as a highly prevalent and largely under-recognized and untreated class of OCD patients. Furthermore, our data suggest that "cyclothymic OCD" could represent a distinct form of OCD. More attention should be paid to it in research and clinical practice.

Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP).

BACKGROUND: This paper presents the methodology and clinical data in mid-stream from a French multi-center study (EPIDEP) in progress on a national sample of patients with DSM-IV major depressive episode (MDE). The aim of EPIDEP is to show the feasibility of validating the spectrum of soft bipolar disorders by practising clinicians. In this report, we focus on bipolar II (BP-II). METHOD: EPIDEP involves training 48 French psychiatrists in 15 sites; construction of a common protocol based on the criteria of DSM-IV 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 Evaluation of Affective Temperaments (based on Akiskal-Mallya), self-rated Cyclothymia Scale (Akiskal), family history (Research Diagnostic Criteria); and prospective follow-up. RESULTS: Results are presented on 250 (of the 537) MDE patients studied thus far during the acute phase. The rate of BP-II disorder which was 22% at initial evaluation, nearly doubled (40%) by systematic evaluation. As expected from the selection of MDE by uniform criteria, inter-group comparison between BP-II vs unipolar showed no differences on the majority of socio-demographic parameters, clinical presentation and global intensity of depression. Despite such uniformity, key characteristics significantly differentiated BP-II from unipolar: younger age at onset of first depression, higher frequency of suicidal thoughts and hypersomnia during index episode, higher scores on Hypomania Checklist and cyclothymic and irritable temperaments, and higher switching rate under current treatment. Eighty-eight percent of cases assigned to cyclothymic temperament by clinicians (with a cut-off of 10/21 items on self-rated cyclothymia) were recognized as BP-II. Evaluation of this temperament by clinician and patient correlated at a highly significant level (r=0.73; p <0.0001). Cyclothymia and hypomania were also correlated significantly (r=0.51; p < 0.001). LIMITATION: In a study conducted in diverse clinical settings, it was not possible to assure that clinicians making affective diagnoses were blind to the various temperamental measures. However, bias was minimized by the systematic and/or semi-structured nature of all evaluations. CONCLUSION: With a systematic search for hypomania, 40% of major depressive episodes were classified as BP-II, of which only half were known to the clinicians at study entry. Cyclothymic temperamental dysregulation emerged as a robust clinical marker of BP-II disorder. These data indicate that clinicians in diverse practice settings can be trained to recognize soft bipolarity, leading to changes in diagnostic practice at a national level.

Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN).

BACKGROUND: This research derives from the French national multisite collaborative study on the clinical epidemiology of mania (EPIMAN). Our aim is to establish the validity of dysphoric mania along a "spectrum of mixity" extending into mixed mania with subthreshold depressive manifestations; to demonstrate the feasibility of obtaining clinically meaningful data on this entity on a national level; and to characterize the contribution of temperamental attributes and gender in its origin. METHODS: EPIMAN involves training 23 French psychiatrists in four different sites, representing four regions of France; to rigorously apply a common protocol deriving from the criteria of DSM-IV and McElroy et al.; the use of such instruments as the Beigel-Murphy, Ahearn-Carroll, modified HAM-D; and measures of affective temperaments based on the Akiskal-Mallya criteria; obtaining data on comorbidity, and family history (according to Winokur's approach as incorporated into the FH-RDC); and prospective follow-up for at least 12 months. The present report concerns the clinical and temperamental features of 104 manic patients during the acute hospital phase. RESULTS: Dysphoric mania (DM defined conservatively with fullblown depressive admixtures of five or more symptoms) occurred in 6.7%; the rate of dysphoric mania defined broadly (DM, presence of > or = 2 depressive symptoms) was 37%. Depressed mood and suicidal thoughts had the best positive predictive values for mixed mania. In comparison to pure mania (0-1 depressive symptoms), DM was characterized by female over-representation; lower frequency of such typical manic symptomatology as elation, grandiosity, and excessive involvement; higher prevalence of associated psychotic features; higher rate of mixed states in first episodes; and complex temperamental dysregulation along primarily depressive, but also cyclothymic, and irritable dimensions; such irritability was particularly apparent in mixed mania at the lowest threshold of depressive admixtures of two symptoms only. LIMITATION: In a study involving hospitalized affectively unstable psychotic patients, it was difficult to assure that psychiatrists making the clinical diagnoses would be blind to the temperamental measures. However, bias was minimized by the systematic and/or semi-structured nature of all evaluations. CONCLUSIONS: Mixed mania, defined cross-sectionally by the simultaneous presence of at least two depressive symptoms, represents a prevalent and clinically distinct form of mania. Subthreshold depressive admixtures with mania actually appear to represent the more common expression of dysphoric mania. Moreover, an irritable dimension appears to be relevant to the definition of the expression of mixed mania with the lowest threshold of depressive symptoms. Neither an extreme, nor an endstage of mania, "mixity" is best conceptualized as intrusion of mania into its "opposite" temperament - especially that defined by lifelong depressive traits - and favored by female gender. These data suggest that reversal from a temperament to an episode of "opposite" polarity represents a fundamental aspect of the dysregulation that characterizes bipolar disorder. In both men and women with hyperthymic temperament, there appears "protection" against depressive symptom formation during a manic episode which, accordingly, remains relatively "pure". Because men have higher rates of this temperament, pure mania is overrepresented in men; on the other hand, the depressive temperament in manic women seems to be a clinical marker for the well-known female tendency for depression, hence the higher prevalence of mixed mania in women.

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.