Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.

Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1(-/-) mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1(-/-) mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1(-/-) prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1(-/-) mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1(-/-) mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression.

Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine.

Mood disorders in eating disorder patients: Prevalence and chronology of ONSET.

OBJECTIVES: In a clinical population, we estimated the frequency of mood disorders among 271 patients suffering from Anorexia Nervosa (AN) and Bulimia Nervosa (BN) in comparison to a control group matched for age and gender. METHOD: The frequency of mood disorders was measured using the Mini International Neuropsychiatric Interview (MINI), DSM-IV version. RESULTS: Mood disorders were more frequent among eating disorder (ED) patients than among controls, with a global prevalence of the order of 80% for each ED group. The majority of the mood disorders comorbid with ED were depressive disorders (MDD and dysthymia). The relative chronology of onset of these disorders was equivocal, because mood disorders in some cases preceded and in others followed the onset of the eating disorders. LIMITATIONS: Our sample was characterized by patients with severe ED and high comorbidities, and thus do not represent the entire population of AN or BN. This also may have resulted in an overestimation of prevalence. CONCLUSION: Mood disorders appear significantly more frequently in patients seeking care for ED than in controls. These results have implications for the assessment and treatment of ED patients, and for the aetio-pathogenesis of these disorders.

[Traumatic events and stress responses: the role of oxytocin and attachment]. / Evénements traumatiques et réponses de stress: le rôle de l'ocytocine et de l'attachement.

Being repeatedly confronted to very difficult situations since childhood influences the way indivuals will later respond to even mildly stressful events. The hypothalamic-pituitary-adrenal axis (HPA) is a complex system implicated in regulating neuroendocrine responses to stress. Its activation produces among others the <

Profile of male adolescents with conduct disorder on intellectual efficacy, cognitive flexibility, cognitive coping, impulsivity and alexithymia: A comparison with high-risk controls

Background and Objectives: To specify which of the documented cognitive and emotional deficits characterize adolescents with conduct disorder (CD) compared with high-risk controls. Methods: High-risk adolescent males with and without CD were compared on intellectual efficiency, cognitive flexibility, impulsivity, alexithymia, and cognitive coping strategies. Substance use was controlled for in analyses. Results: Both groups showed normal intellectual efficiency and cognitive flexibility, as well as heightened alexithymia and behavioral impulsivity. Youths with CD evidenced more self-defeating and black-and-white thinking under stress, and more acting-out under negative affect, than those without CD. Conclusions: Deficits specific to CD resided in facets of emotional functioning and cognitive coping that might be targeted by a coping skills intervention (AU)

[Adolescent brain maturation]. / La maturation cérébrale à l'adolescence.

Recent progress in neuroscience has yielded major findings regarding brain maturation during adolescence. Unlike the body, which reaches adult size and morphology during this period, the adolescent brain is still maturing. The prefrontal cortex appears to be an important locus of maturational change subserving executive functions that may regulate emotional and motivational issues. The recent expansion of the adolescent period has increased the lag between the onset of emotional and motivational changes activated by puberty and the completion of cognitive development-the maturation of self-regulatory capacities and skills that are continuing to develop long after puberty has occurred. This "disconnect" predicts risk for a broad set of behavioral and emotional problems. Adolescence is a critical period for high-level cognitive functions such as socialization that rely on maturation of the prefrontal cortex. Intervention during the period of adolescent brain development provides opportunities and requires an interdisciplinary approach.

Quetiapine in adolescents with non-affective psychotic disorders: an open-label trial.

INTRODUCTION: There is a need for more studies on the clinical effectiveness, tolerability and pharmacokinetics of atypical antipsychotics in adolescents with psychotic disorders, as this represents a vulnerable and difficult population to treat. According to recent concerns regarding disabling side effects of antipsychotics, particularly weight gain, further monitoring of their safety profiles is needed. This situation prompted the authors to carry out an investigation on the clinical effectiveness of quetiapine in psychotic adolescents. METHODS: 23 adolescents (13-18 years old) with psychotic disorders participated in a 12-week open label trial, including 6 visits assessing clinical efficacy, tolerability and safety of quetiapine (50-750 mg daily). RESULTS: Adolescents were treated with lower doses compared to adults. Significant decreases in CGI and PANSS total scores were observed after both 4 and 12 weeks of quetiapine treatment compared to baseline. Sedation was the main adverse effect, but medication was generally well tolerated. Irregular compliance, (as assessed by pill counts, a questionnaire and by plasma quetiapine concentration monitoring), and alcohol and/or cannabis consumption were factors identified in this study which add to the difficulty in treating this population. DISCUSSION: The results of the present study help to consolidate evidence of the usefulness of quetiapine as a treatment for adolescents with psychotic disorders. However, this study also highlights the issues encountered in treating this group, including the presence of comorbidities such as drug abuse.

Oxytocin response to an experimental psychosocial challenge in adults exposed to traumatic experiences during childhood or adolescence.

Long-term implications of the exposure to traumatizing experiences during childhood or adolescence, such as sexual abuse, or cancer, have been documented, namely the subjects' response to an acute stress in adulthood. Several indicators of the stress response have been considered (e.g. cortisol, heart rate). Oxytocin (OT) response to an acute stress of individuals exposed to trauma has not been documented. Eighty subjects (n=26 women who had experienced episodes of child abuse, n=25 men and women healthy survivors of cancer in childhood or adolescence, and 29 controls) have been submitted to a laboratory session involving an experimental stress challenge, the Trier social stress test. Overall, there was a clear OT response to the psychosocial challenge. Subjects having experienced a childhood/adolescence life-threatening illness had higher mean levels of OT than both abused and control subjects. There was a moderate negative relationship between OT and salivary cortisol. It is suggested that an acute stress stimulates OT secretion, and that the exposure to enduring life-threatening experiences in childhood/adolescence has long-lasting consequences regarding the stress system and connected functions, namely the activation of OT secretion. Better knowledge of such long-term implications is important so that to prevent dysregulations of the stress responses, which have been shown to be associated to the individual's mental health.

[Adolescent psychosis, can neuroscience improve prediction?]. / Psychoses à l'adolescence, les neurosciences améliorent-elles la prédiction?

Developments in the field of neuroscience have created a high level of interest in the subject of adolescent psychosis, particularly in relation to prediction and prevention. As the medical practice of adolescent psychosis and its treatment is characterised by a heterogeneity which is both symptomatic and evolutive, the somewhat poor prognosis of chronic development justifies the research performed: apparent indicators of schizophrenic disorders on the one hand and specific endophenotypes on the other are becoming increasingly important. The significant progresses made on the human genome show that the genetic predetermination in current psychiatric pathologies is complex and subject to moderating effects and there is therefore significant potential for nature-nurture interactions (between the environment and the genes). The road to be followed in researching the phenotypic expression of a psychosis gene is long and winding and is susceptible to many external influences at various levels with different effects. Neurobiological, neurophysiological, neuropsychological and neuroanatomical studies help to identify endophenotypes, which allow researchers to create identifying "markers" along this winding road. The endophenotypes could make it possible to redefine the nosological categories and enhance understanding of the physiopathology of schizophrenia. In a predictive approach, large-scale retrospective and prospective studies make it possible to identify risk factors, which are compatible with the neurodevelopmental hypothesis of schizophrenia. However, the predictive value of such markers or risk indicators is not yet sufficiently developed to offer a reliable early-detection method or possible schizophrenia prevention measures. Nonetheless, new developments show promise against the background of a possible future nosographic revolution, based on a paradigm shift. It is perhaps on the basis of homogeneous endophenotypes in particular that we will be able to understand what protects against, or indeed can trigger, psychosis irrespective of the clinical expression or attempts to isolate the common genetic and biological bases according to homogeneous clinical characteristics, which have to date, proved unsuccessful.

[School refusal]. / Le refus scolaire.

Pediatrician are often questioned by school refusal which relies on a wide range of psychopathological features and necessitates specific approaches. This disabling condition remains underestimated and is still increasing. A poor prognosis associated with a prolonged school absence is the common hallmark of school refusals, regardless of its heterogeneity. Its seriousness warrants early identification and prompt intervention by childhood healthcare professionals, teachers and social workers. A specialized treatment is needed, closely linked with families and school. Promising developments come from a functional rather than symptomatic concept of school refusal. They offer tailored interventions which fit the clinical diversity of school refusals. After a brief historical summary and current definitions of school refusal, the authors review the main clinical features and comorbidity before taking up treatment modalities.

[Are anxiety or depressive disorders more frequent among one of the anorexia or bulimia nervosa subtype?]. / La fréquence des troubles anxio-dépressifs diffère-t-elle entre les types diagnostiques d'anorexie mentale et de boulimie?

UNLABELLED: Our objective was to answer the following question: are there differences between diagnostic groups of eating disorders (ED) for the prevalence of depressive and anxiety disorders, when clinical differences between the groups are taken into account (ie age of subjects, ED duration, inpatient or outpatient status, and Body Mass Index)? METHOD: We evaluated the frequency of anxiety disorders and depressive disorders in 271 subjects presenting with a diagnosis of either anorexia nervosa or bulimia, using the Mini International Neuropsychiatric Interview (MINI), DSM IV version. We compared the prevalences between sub-groups of anorexics (AN-R and AN-BN), between sub-groups of bulimics (BN-P and BN-NP) and between anorexics and bulimics while adjusting for the variables defined below. RESULTS: Current or lifetime comorbidity of anxiety and depressive disorders did not differ between AN-Rs and AN-BNs, nor between BN-Ps and BN-NPs. Only current diagnoses of agoraphobia and obsessive-compulsive disorder were significantly more frequent in anorexics than in bulimics. CONCLUSION: The greater frequency of comorbidity between obsessive-compulsive disorder and AN compared to BN, already well documented, is not questioned. The remaining anxiety disorders are equally frequent among all the diagnostic types of ED.

[Is depressive disorder linked to anxiety disorder among anorexics and bulimics?]. / L'existence d'un épisode dépressif majeur est-elle liée à la présence de troubles anxieux chez les anorexiques et les boulimiques?

UNLABELLED: The primaty objective is to determine whether the presence anxiety disorders is related to depressive comorbidity in subjects suffering from ED, while taking into account certain variables which may be related to depression [subjects' age, ED duration, prior incidents of anorexia nervosa in BN subjects, inpatient or outpatient status, nutritional state (as measured by Body Mass Index or BMI)]. Our secondary objective is to evaluate the relative chronology of the onset of anxiety disorders and depressive disorders in anorexic and bulimic subjects. METHOD: We evaluated the frequency of depressive disorders in 271 subjects presenting with a diagnosis of either anorexia nervosa or bulimia, using the Mini International Neuropsychiatric Interview (MINI), DSM IV version. RESULTS: While univariate analyses show that nearly all anxiety disorders are related to major depressive episode (MDE), a separate analysis of each anxiety disorder reveals that they do not all have the same influence in terms of risk of onset of MDE in anorexics and bulimics, when adjusted for univariate variables related to MDE (subjects' age, ED duration, prior incidents of anorexia nervosa in BN subjects, inpatient or outpatient status, nutritional state). Current generalized anxiety is significantly related to lifetime presence of MDE in AN subjects, and to current MDE in AN and BN subjects. Generalized anxiety is the most frequent disorder in AN and BN subjects to according our study; it also appears to be one of the principal predictive factors for MDE, which is 2.4 to 4.2 times more frequent when GAD is present. Diagnosis of OCD has its own particular effect on lifetime risk for MDE in AN subjects, regardless of GAD: it increases the risk of depression by 3.5. It is one of the most frequent anxiety disorders among AN subjects, present in nearly a quarter of them. In bulimics, when GAD is excluded, two factors are related to current diagnosis of MDE: panic disorder and subjects' inpatient or outpatient status. Hospitalized bulimics are diagnosed with current MDE 4.4 times more often than those seen as.

[Alexithymia, depression and drug addiction]. / Alexithymie et toxicomanie:

Alexithymia is a multidimensional concept associating an emotional component focused on the difficulty in identifying and describing feelings and a cognitive one centred on the use of a concrete and poorly introspective way of thinking. Alexithymia can be assessed by self-assessment instruments and in particular by the 20 items version of the Toronto Alexithymia Scale (TAS-20). Depressive disorders have complex relationships with the construct of alexithymia and there exist few experimental works on the subject. Epidemiological studies frequently raise an overlap between alexithymia and depression, in particular in the context of addiction. The main aim of this study was to confirm the high prevalence of alexithymia among drug addicted patients taking into account socio-demographic variables (sex, age, social and economic categories). The second aim of the study was to investigate the relationships between alexithymia and depression among drug addicted patients. A sample of 128 drug addicted patients answering DSM IV criteria of dependence to a psycho-active substance (alcohol excluded) was paired according to socio-demographic variables to a control sample of 128 normal subjects. Diagnostic assessment was made using the Mini International Neuropsychiatric Interview (MINI). Alexithymia and depression were assessed with the TAS-20 and with the short version of the Beck Depression Inventory (BDI-13). The results confirm the high prevalence of alexithymia among drug addicted patients (43.5%) compared to controls (24.6%). This difference is based namely on the emotional component of alexithymia, the cognitive component failing to show any difference between the two samples. Moreover, alexithymia appears to be independent from socio-demographic variables in our sample of drug addicted patients; 66.4% of drug addicted patients presents a depressive symptomatology (which is significantly more important in female patients), compared to 26% of the controls. Studies using the TAS and the BDI with 21 items have shown that from 10 to 20% of the variance of alexithymia is explained by depression. Our own results show a shared variance of 20% between the TAS-20 and the BDI, going in the direction of a moderated correlation between alexithymia and depressive symptomatology. Moreover, when we retain only subjects without depressive symptomatology at BDI, drug addicted (n=42) are not any more alexithymic than controls (n=114). Our results plead for a positive association between depression and alexithymia in drug addicted, depressed or healthy subjects. Alexithymia and depression would be two associated dimensions, the emotional component explaining alone this association. The emotional component of the alexithymia would be thymo-dependent, whereas the cognitive component (externally oriented thought) would be independent and constitute a stable clinical feature. These results are concordant with other studies in the literature suggesting that alexithymia in its emotional component is supported by depression. Alexithymia thus did not appear as an autonomous dimension which would discriminate between drug addicted and controls, independently of the absence of a depressive state. The Authors discuss the complexity of the relationships between alexithymia and depression and the correlations between TAS and BDI scales especially for the factor Difficulty Identifying Feelings. These results deserve further studies. The cross-sectional nature of this study do not allow to establish if alexithymia is a subjacent and preexistent in the form of a psychopathological dimension in addictive behaviours, so supporting its emergence, and/or if it develops once the dependence is installed and chronicized. Longitudinal studies remain to be realised.

Personality trait risk factors for attempted suicide among young women with eating disorders.

OBJECTIVE: - Clinical observations and a review of the literature led us to hypothesize that certain personality and character traits could provide improved understanding, and thus improved prevention, of suicidal behaviour among young women with eating disorders. METHOD: - The clinical group consisted of 152 women aged between 18 and 24 years, with DSM-IV anorexia nervosa/restrictive type (AN-R = 66), anorexia nervosa/purging type (AN-P = 37), bulimia nervosa/non-purging type (BN-NP = 9), or bulimia nervosa/purging type (BN-P = 40). The control group consisted of 140 subjects. The assessment measures were the Minnesota Multiphasic Personality Inventory-second version (MMPI-2) scales and subscales, the Beck Depression Inventory (BDI) used to control for current depressive symptoms, plus a specific questionnaire concerning suicide attempts. RESULTS: - Suicide attempts were most frequent in subjects with purging behaviour (30.0% for BN-P and 29.7% for AN-P). Those attempting suicide among subjects with eating disorders were mostly students (67.8%). For women with AN-R the scales for 'Depression' and 'Antisocial practices' represented significant suicidal risk, for women with AN-P the scales for 'Hysteria', 'Psychopathic deviate', 'Shyness/Self-consciousness', 'Antisocial Practices', 'Obsessiveness' and 'Low self-esteem' were risk indicators and for women with BN-P the 'Psychasthenia', 'Anger' and 'Fears' scales were risk indicators. CONCLUSION: - This study provides interesting results concerning the personality traits of young women with both eating disorders and suicidal behaviour. Students and those with purging behaviour are most at risk. Young women should be given more attention with regard to the risk of suicide attempts if they: (a). have AN-R with a tendency to self-punishment and antisocial conduct, (b). have AN-P with multiple physical complaints, are not at ease in social situations and have antisocial behaviour, or (c). if they have BN-P and tend to be easily angered with obsessive behaviour and phobic worries. The MMPI-2 is an interesting assessment method for the study of traits indicating a risk of suicidal behaviour in young subjects, after controlling for current depressive pathology.

Predictive factors of social disability in anorexic and bulimic patients.

OBJECTIVES: The purpose of this study was to determine whether subjects suffering from anorexia nervosa (AN) or bulimia nervosa (BN) would demonstrate more severe social disability than a control group; and whether social disability could be best explained as a function of the eating disorder itself or as a function of comorbid anxiety or depressive disorders. METHOD: Subjects were 166 AN subjects, 105 BN subjects and 271 control subjects matched for age, sex and socio-economic status. Prevalence of anxiety or depressive disorders was assessed (through the Mini International Neuropsychiatric Interview), and social functioning was measured (through the Groningen scale). RESULTS: The majority of AN and BN subjects demonstrated social disability in the "social role" (leisure time, time spent with friends) and the "occupational role" (work or educational activities). A regression analysis was employed to uncover predictive factors of social disability. Eating disorders (AN and BN), anxiety disorders and depression accounted for a large portion of social disability. DISCUSSION: Anxiety and depressive disorders appear to play an important role in the type of social disability demonstrated in eating disorder patients. Therapeutic implications are discussed.

Evaluation of the Adolescent Drug Abuse Diagnosis instrument in a Swiss sample of drug abusers.

OBJECTIVE: The aim of this study was to evaluate a French language version of the Adolescent Drug Abuse Diagnosis (ADAD) instrument in a Swiss sample of adolescent illicit drug and/or alcohol users. PARTICIPANTS AND SETTING: The participants in the study were 102 French-speaking adolescents aged 13-19 years who fitted the criteria of illicit drug or alcohol use (at least one substance--except tobacco--once a week during the last 3 months). They were recruited in hospitals, institutions and leisure places. Procedure. The ADAD was administered individually by trained psychologists. It was integrated into a broader protocol including alcohol and drug abuse DSM-IV diagnoses, the BDI-13 (Beck Depression Inventory), life events and treatment trajectories. RESULTS: The ADAD appears to show good inter-rater reliability; the subscales showed good internal coherence and the correlations between the composite scores and the severity ratings were moderate to high. Finally, the results confirmed good concurrent validity for three out of eight ADAD dimensions. CONCLUSIONS: The French language version of the ADAD appears to be an adequate instrument for assessing drug use and associated problems in adolescents. Despite its complexity, the instrument has acceptable validity, reliability and usefulness criteria, enabling international and transcultural comparisons.

[Psychoactive drug use in a declared non-addicted control sample and comorbidity. Results of a study in 860 French-speaking subjects]. / Consommation de substances psycho-actives dans une population témoin déclarée non addictive et co-morbidité. Résultats d'une étude chez 860 sujets francophones.

AIMS: This study, conducted within the framework of a broader research program of the INSERM 494013 Dependence Network, was designed to estimate illicit drug use and tobacco smoking in a declared non-addicted sample and to determine whether illicit drug users differ from non-users in terms of comorbidity. METHODS: The study was conducted in an "all and sundry" sample of subjects. Patterns of drug use and comorbid factors (psychiatric disorders, suicide attempts, repeated accidents, social inadaptation) were assessed using a semi-structured interview (heteroevaluation, MINI DSM IV interview, Gröningen). RESULTS: Among 860 subjects, 107 (12.4%) used illicit drugs and 26 of these 107 (24.3%) were dependent users or abusers. Specific analysis of non-dependent non-abuser subjects who had used illicit drugs (70 occasional and 11 regular users) showed a higher rate of use in younger subjects (12.7% in the 15-24 year group, 5.7% in the 24-49 year group) and men. Except for repeated accidents (OR=5.5 [1.6-18.5]), comorbid disorders were not more frequent in non-users than in users. CONCLUSION: Besides use for recreational purposes, the rate of use of illicit drugs with abuse or dependence was high in our non-clinical sample. Although no specific comorbid psychiatric disorders were identified among non-dependent non-abuser subjects who had used illicit drugs, the frequency of repeated accidents evidenced the ill-fated side effects of illicit drugs and/or the specific biopsychological vulnerability of these subjects. This highlights the importance of not neglecting drug abuse.

Psychoactive substance consumption in eating disorders.

Research investigating the comorbidity between eating disorders and substance-use disorders have reported positive but contrasting results. The aim of this study was to further explore this association by studying patterns of consumption of the entire range of psychoactive substances (alcohol, specific drugs, prescribed psychotropics) in a large sample (N=271) of eating-disorder DSM-IV subtypes. Results show that subjects suffering from anorexia of the restrictive type show significantly less drug-consumption behaviors and alcohol abuse and/or dependence disorders than purging anorexic and bulimic subjects. No difference was found in the total consumption of psychotropics among the four groups of eating disorders. However, more than half of eating-disorder subjects are regular consumers of psychotropics. Among these regular consumers, bulimics self-prescribe and increase their doses of psychotropics significantly more than anorexics. Features of impulsivity that are associated with purging and bulimic behaviors could play a specific role in these patterns of comorbidity and account for such differences.