Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study

Citalopram is a chiral antidepressant drug. Its eutomer, S-citalopram (escitalopram), has recently been introduced as an antidepressant. In an open pilot study, four outpatients and two inpatients with a major depressive episode (ICD-10), and who were nonresponders to a 4-week pretreatment with 40-60 mg/day citalopram, were comedicated for another 4-week period with carbamazepine (200-400 mg/day). Some of the patients suffered also from comorbidities: Phobic anxiety disorder with panic attacks (n=2), generalised anxiety disorder, alcohol abuse, dependent personality disorder, hypertension (n=1). After a 4-week augmentation therapy with carbamazepine, a significant (P<0.03) decrease of the plasma concentrations of S-citalopram and R-citalopram, by 27 and 31%, respectively, was observed. Apparently, the probable induction of CYP3A4 by carbamazepine results in a nonstereoselective increase in N-demethylation of citalopram. Moreover, there was a significant (P<0.03) decrease of the ratio S/R-citalopram propionic acid derivative, the formation of it being partly regulated by MAO-A and MAO-B. Already, within 1 week after addition of carbamazepine, there was a slight but significant (P<0.03) decrease of the MADRS depression scores, from 27.0+/-7.7 (mean+/-S.D.) to 23.3+/-6.6, and the final score on day 56 was 18.8+/-10.9. The treatment was generally well tolerated. There was no evidence of occurrence of a serotonin syndrome. After augmentation with carbamazepine, treatment related adverse events were: Nausea in one case, diarrhea in one case, and rash in two cases. In conclusion, the results of this pilot study suggest that carbamazepine augmentation of a citalopram treatment in previous nonresponders to citalopram may be clinically useful, but that in addition carbamazepine can lead to a decrease of the plasma concentrations of the active enantiomer escitalopram.

Defining substance use disorders: do we really need more than heavy use?

AIMS: The aim of the study was to explore whether the concept of heavy substance use over time can be used as definition of substance use disorder. METHODS: Narrative review. RESULTS: Heavy use over time clearly underlies the neurobiological changes associated with current thinking of substance use disorders. In addition, there is evidence that heavy use over time can explain the majority of social problems and of burden of disease (morbidity and mortality). A definition of substance use disorders via heavy use over time would avoid some of the problems of current conceptualizations, for instance the cultural specificity of concepts such as loss of control. Finally, stressing the continuum of use may avoid the high level of stigmatization currently associated with substance use disorders. CONCLUSION: 'Heavy substance use over time' seems to be a definition of substance use disorders in line with results of basic research and epidemiology. Additionally, it reduces stigmatization. This approach should thus be further explored.

How to screen for problematic cannabis use in population surveys: an evaluation of the Cannabis Use Disorders Identification Test (CUDIT) in a Swiss sample of adolescents and young adults.

BACKGROUND/AIMS: Cannabis use is a growing challenge for public health, calling for adequate instruments to identify problematic consumption patterns. The Cannabis Use Disorders Identification Test (CUDIT) is a 10-item questionnaire used for screening cannabis abuse and dependency. The present study evaluated that screening instrument. METHODS: In a representative population sample of 5,025 Swiss adolescents and young adults, 593 current cannabis users replied to the CUDIT. Internal consistency was examined by means of Cronbach's alpha and confirmatory factor analysis. In addition, the CUDIT was compared to accepted concepts of problematic cannabis use (e.g. using cannabis and driving). ROC analyses were used to test the CUDIT's discriminative ability and to determine an appropriate cut-off. RESULTS: Two items ('injuries' and 'hours being stoned') had loadings below 0.5 on the unidimensional construct and correlated lower than 0.4 with the total CUDIT score. All concepts of problematic cannabis use were related to CUDIT scores. An ideal cut-off between six and eight points was found. CONCLUSIONS: Although the CUDIT seems to be a promising instrument to identify problematic cannabis use, there is a need to revise some of its items.

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models.

The integrity of central and peripheral nervous system myelin is affected in numerous lipid metabolism disorders. This vulnerability was so far mostly attributed to the extraordinarily high level of lipid synthesis that is required for the formation of myelin, and to the relative autonomy in lipid synthesis of myelinating glial cells because of blood barriers shielding the nervous system from circulating lipids. Recent insights from analysis of inherited lipid disorders, especially those with prevailing lipid depletion and from mouse models with glia-specific disruption of lipid metabolism, shed new light on this issue. The particular lipid composition of myelin, the transport of lipid-associated myelin proteins, and the necessity for timely assembly of the myelin sheath all contribute to the observed vulnerability of myelin to perturbed lipid metabolism. Furthermore, the uptake of external lipids may also play a role in the formation of myelin membranes. In addition to an improved understanding of basic myelin biology, these data provide a foundation for future therapeutic interventions aiming at preserving glial cell integrity in metabolic disorders.

Non-Compressive Disorders of the Chiasm.

Chiasmal dysfunction produces a characteristic clinical picture, regardless of the mechanism. In most cases a compressive lesion is the cause. In occasional cases, however, no such extrinsic mass is found and other possible etiologies must be explored. In some of these cases, the pathologic process is identifiable with appropriate neuroimaging. For example, inflammation, infiltrative tumors, and radiation necrosis produce intrinsic chiasmal enhancement. Chiasmal ischemia may require specialized magnetic resonance (MR) sequences for diagnosis. Chiasmal hemorrhage, trauma and chiasmal herniation typically produce distinctive changes on noncontrasted imaging. In cases of metabolic insult, either toxic or hereditary, radiographic changes are typically absent. In each of these, the correct diagnosis can usually be made with a combination of clinical and radiographic features.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

The genetic basis of sleep disorders.

The contribution of genes, environment and gene-environment interactions to sleep disorders is increasingly recognized. Well-documented familial and twin sleep disorder studies suggest an important influence of genetic factors. However, only few sleep disorders have an established genetic basis including four rare diseases that may result from a single gene mutation: fatal familial insomnia, familial advanced sleep-phase syndrome, chronic primary insomnia, and narcolepsy with cataplexy. However, most sleep disorders are complex in terms of their genetic susceptibility together with the variable expressivity of the phenotype even within a same family. Recent linkage, genome-wide and candidate gene association studies resulted in the identification of gene mutations, gene localizations, or evidence for susceptibility genes and/or loci in several sleep disorders. Molecular techniques including mainly genome-wide linkage and association studies are further required to identify the contribution of new genes. These identified susceptibility genetic determinants will provide clues to better understand pathogenesis of sleep disorders, to assess the risk for diseases and also to find new drug targets to treat and to prevent the underlying conditions. We reviewed here the role of genetic basis in most of key sleep disorders.

Rôle du médecin interniste ou du généraliste dans le diagnostic et le suivi d'une collagénose [Family physician and connective tissue disorders].

The exact place of the family physician in the diagnosis and management of connective tissue disease is poorly studied moreover will essentially depend on the health system and the organization of medical network of each country. Connective tissue diseases are rare and complex diseases that require in all cases referral to specialists for their diagnosis as well as monitoring. All patients must still keep a family doctor whose importance increases more and more as our specialized treatments prolong survival of patients who become chronically ill with multi-organic sequelae. A closely interaction between the various specialists and family physicians is necessary to ensure a good long-term follow-up.

A prospective study of predictors of poststroke depression.

OBJECTIVE: To investigate the association between early depressive behavior after stroke onset and occurrence of poststroke depression (PSD) at 3- and 12-month follow-up evaluations. METHODS: The study prospectively included 273 patients with first-ever single uncomplicated ischemic stroke. In the stroke unit, nurses scored crying, overt sadness, and apathy daily using an observational method to include patients with comprehension deficits. The Barthel Index was used to assess disability. Follow-up evaluation at months 3 and 12 included psychiatric assessment based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. RESULTS: Crying (19.8%), overt sadness (50.5%), and apathy (47.6%) were observed. Of the patients observed crying, 4 showed pathologic crying, 19 emotionalism, and 12 catastrophic reactions. Crying and overt sadness, but not apathy, were associated with a subjective experience of depression (p < 0.05). Thirty of 52 (58%) patients observed crying, 12 of 19 (63%) patients with emotionalism, and 5 of 12 (41%) patients with catastrophic reactions developed PSD within the first year. Multiple logistic regression analysis showed that only severe functional disability (odds ratio [OR], 4.31; 95% CI, 2.41 to 7.69), crying behaviors (OR, 2.66; 95% CI, 1.35 to 5.27), and an age <68 years (OR, 2.32; 95% CI, 1.30 to 4.13) were (p < 0.05) predictors of late PSD development (13% of the variance). CONCLUSIONS: In the stroke unit, crying and overt sadness are more reliable indicators of depressed mood than apathy. In patients with first-ever stroke, crying behaviors soon after stroke, a younger age, and severe disability are predictors of poststroke depression occurrence within the first year after stroke onset.

Transgenerational transmission of trauma in families of Holocaust survivors: The consequences of extreme family functioning on resilience, Sense of Coherence, anxiety and depression.

BACKGROUND: The psychological transmission of the noxious effects of a major trauma from one generation to the next remains unclear. The present study aims to identify possible mechanisms explaining this transmission among families of Holocaust Survivors (HS). We hypothesized that the high level of depressive and anxiety disorders (DAD) among HS impairs family systems, which results in damaging coping strategies of their children (CHS) yielding a higher level of DAD. METHODS: 49 CHS completed the Resilience Scale for Adults, the Hopkins Symptom Check List-25, the 13-Item Sense of Coherence (SOC) scale, and the Family Adaptability and Cohesion Scale. We test a mediation model with Family types as the predictor; coping strategies (i.e. Resilience or SOC) as the mediator; and DAD as the outcome variable. RESULTS: Results confirm that the CHS׳ family types are more often damaged than in general population. Moreover, growing in a damaged family seems to impede development of coping strategies and, therefore, enhances the occurrence of DAD. LIMITATIONS: The present investigation is correlational and should be confirmed by other prospective investigations. CONCLUSIONS: At a theoretical level we propose a mechanism of transmission of the noxious effects of a major trauma from one generation to the next through family structure and coping strategies. At a clinical level, our results suggest to investigate the occurrence of trauma among parents of patients consulting for DAD and to reinforce their coping strategies.