Trial of an Intervention for adolescents with moderate to severe symptoms of depression using the beyondblue framework

Abstract Objective: Adolescence is a period of development where rates of psychopathology increase significantly (Steiner & Feldman, 1996). Further, mental disorders such as depression have been named the major burden of disease amongst adolescent populations (Australian Institute of Health and Wellbeing [AIHW], 2007). There is a need to develop cost effective and accessible approaches to the prevention and early intervention of depression, including school-based programmes (Sawyer et al., 2000). Targeted interventions as opposed to universal prevention programmes appear to be generally offering more favourable short and long-term outcomes regarding the reduction of depressive symptoms (Sheffield et al., 2006). Based upon these research findings, the primary aims of this thesis were: 1. To take existing, theoretically driven processes used in the beyondblue Schools Research Initiative designed for students in grades 8 to 10, and to deliver them as a targeted intervention for students in grades 10 to 12 who had been screened for symptoms of depression; and 2. To conduct exploratory research into the impact of this targeted intervention on student symptomatology and general functioning before and after completion of the programme. Method: Forty-seven students aged between 14-17 years (M = 15.25 years, SD = 0.76) from a Catholic college north of Brisbane were recruited for this pilot study. As part of usual college processes all students in grades 10 to 12 were screened in order to determine the socio-emotional needs within the student population and to make an attempt to address these. Students who reported moderate to extremely severe scores on at least one of the Depression, Anxiety, and Stress Scale (DASS: Lovibond & Lovibond, 1995) subscales were then offered the opportunity to participate in this targeted programme, with the requirement of consent from students and their parents. Students for whom consent was not gained, were offered the options of attending internal individual counselling at the college or referrals to an external agency, such as a private counsellor/psychologist or the local Child and Youth Mental Health Service. Those who did consent to participate were divided into four groups with approximately equal numbers and then provided the same intervention sessions over an eight-week period. This division into four groups of approximately 12 students was decided upon for the optimum delivery of the programme, with no specific selection criteria used. Students were allocated to a group on receipt of their consent forms. Participants were assessed at pre intervention, post intervention, and follow-up using a number of self-report measures. Two N = 1 case studies were also included demonstrating improvement and mixed results respectively, exploring the possible factors associated with these individual outcomes. Results: The results demonstrated that adolescents experienced significant improvements in symptomatology (depression, anxiety, and anger), their general functioning (self-concept, positive thinking, and negative problem orientation), and the severity of their clinical status over time. Further, student involvement in the programme appears to have had a positive impact upon reported quality of life and help-seeking behaviours. Conclusion: The goal of this research was to explore the effectiveness of the beyondblue Schools Research Initiative materials when applied as part of a targeted intervention. Preliminary results are promising, although further work is required to enhance school-based interventions. Limitations, implications, and directions for future research are also addressed

Corticotropin-releasing factor 2 receptor-deficiency reduces memory and social deficits induced by cocaine

Les travaux de cette thèse visent à étudier le role du système corticotropin-releasing factor (CRF) dans les dysfonctions cognitives, les altérations du comportement social et la vulnérabilité au stress associées à l addiction aux drogues. Les effets de la délétion génétique du récepteur CRF1 ou CRF2 sont examinés dans les tests de reconnaissance d objet et de préférence sociale après une exposition chronique et pendant le sevrage à la cocaine. Le rôle du récepteur CRF2 dans la vulnérabilité au stress qui pourrait précipiter l apparition de déficits cognitifs et sociaux pendant le sevrage prolongé à la cocaine est également étudié.Stimulant-related disorders are characterized by emotional-like, cognitive and social dysfunction that may contribute to the maintenance of the disease. In addition, stimulant use and withdrawal may alter brain stress systems. The corticotropin-releasing factor (CRF) system is a major stress coordinator hypothesized to contribute to substance-related disorders. CRF signalling is mediated by two receptor types, named CRF1 and CRF2. The specific role of each of the CRF receptors in negative affective-like, cognitive and social dysfunction associated with stimulant administration and withdrawal remains largely unknown. The present study demonstrates that the CRF1 receptor-deficiency increases the anxiety-like behaviour induced by intermittent administration of escalating doses of cocaine (5-20 mg/kg, i.p.), as assessed by the elevated plus maze. In addition, the same cocaine regimen induces novel object recognition (NOR) and sociability deficits, which are unaffected by CRF2 receptor-deficiency. However, CRF2 receptor-deficiency effectively shortens the duration of the NOR and sociability deficit induced by cocaine withdrawal. Furthermore, following the apparent recovery of NOR and sociability performances during relative long-term (42 days) cocaine withdrawal, CRF2 receptor-deficiency eliminates the stress-induced re-emergence of NOR and sociability deficit. Stressed cocaine-withdrawn mice show a genotype-independent higher c-fos mRNA expression in the perirhinal cortex, a brain region mediating NOR performance, than stressed drug-naïve mice. However, neither genotype nor drug withdrawal affects the expression of tyrosine hydroxylase in the ventral tegmentale area and the locus coeruleus, CRF in the amygdala and the paraventricular nucleus of the hypothalamus and dynorphin in the nucleus accumbens shell. The latter results suggest that stress vulnerability during long-term cocaine withdrawal is not due to alterations in stress-coping mechanisms. The present study provides initial evidence of a critical role for the CRF system in cognitive and sociability deficits and vulnerability induced by stimulant administration and withdrawal, suggesting new therapeutic strategies for substance-related disorders.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Dépendance aux drogues opiacées (focus sur le système corticotropin-releasing factor)

La prise illicite de drogues opiacées est un problème majeur de santé publique dans le monde. L apparition du syndrome de sevrage aux opiacés (SAO) suite à l arrêt de prise d opiacés est considérée comme élément clef dans la vulnérabilité associée à la rechute de prise d opiacés. En effet le syndrome de SAO est caractérisé par des altérations comportementales et neurobiologiques en réponse au stress qui sont déterminantes dans le phénomène de dépendance aux opiacés. Le système corticotropin-releasing factor (CRF) est un coordinateur central des circuits de réponse au stress par l intermédiaire de ses deux récepteurs le: CRF1 et CRF2. L objectif de cette thèse est de déterminer le rôle du récepteur CRF2 dans l apparition des états affectifs négatifs et des désordres motivationnels impliqués dans la rechute de la consommation de drogues opioïdes lors du SAO.Nous avons démontré par une série d expériences conduite chez des souris invalidées au récepteur CRF2 (CRF2-/-), que la délétion génétique du récepteur CRF2-/- éliminait les états dysphoriques ainsi que les altérations moléculaires induites par le SAO sans détériorer les réponses neuroendocriniennes qui sont primordiales lors des adaptations aux stress associées au sevrage. De surcroît, nous avons trouvé que les souris CRF2-/- entrainées dans une procédure de tâche opérante dirigée vers l obtention d une nourriture palatable, montraient une diminution des troubles motivationnels induits par le SAO. Plusieurs rapports montrent que chez l Homme, les évènements stressants apparaissant lors d une période de sevrage provoquent une rechute de la consommation d alcool ou de drogues. Nous avons développé un modèle murin qui montrait un rétablissement de recherche de nourriture palatable suite à une procédure de stress appliquée pendant une période de SAO. Par ailleurs, nous avons observé un dimorphisme sexuel du rôle du récepteur CRF2 dans le rétablissement de recherche de nourriture palatable, suite au stress, longtemps après un SAO.Les résultats de ce travail de thèse nous permettent de mettre en avant le récepteur CRF2 comme possible cible thérapeutique dans le traitement de la dépendance aux opiacés.Opiate illicit use represents one of the most severe sanitary problems throughout the world. Among humans, the emergence of the opiate withdrawal (OW) syndrome after cessation of opiate intake is considered as one of the key motivational elements that lead to the vulnerability to opiates relapse. Therefore, the OW is characterized by a various alterations of the behavioral and neurobiological homeostasis responses to stress which are determinants in opiate dependence. The Corticotropin-releasing factor (CRF) system is the major coordinator of stress-responsive circuitry. Through its two receptors CRF1 and CRF2, the CRF system has recently emerged as major contributor in the development of components of the OW syndrome. The aim of this thesis is to determine the role of CRF2 receptor in the negative affective states and motivational disorders implicated in opiate relapse during OW.Behavioral and biological experiments were conducted in CRF2 receptor-deficient mice (CRF2-/-). We reported that genetic deletion of the CRF2 receptor eliminates dysphoria and molecular alterations elicited by OW without impairing brain, neuroendocrine and autonomic stress-coping responses to withdrawal. Using behavioral approaches of operant responding to highly palatable food (HPF) we found that CRF2-/- reduces motivational disorders induced by intermittent morphine injections and withdrawal. Finally, we described a mouse model of stress-induced food reinstatement seeking behavior during prolonged OW. Furthermore, we reported a gender dimorphism in the role of the CRF2 receptor in the stress-induced reinstatement of HPF seeking behavior long-lasing after opiate treatment.These findings underscore the importance of CRF2 receptor as possible effective treatment of the critical problem of opiate dependence.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Decreased motivation to eat in mu-opioid receptor-deficient mice.

Altered motivational processes might participate to the physiopathology of eating-related disorders. The endogenous opioid system is thought to mediate the hedonic properties of food intake. To assess the role for the micro-opioid receptor (MOR) pathway in the motivational properties of food intake, in the present study we tested wild-type and MOR-deficient mice (MOR-/-) in a nose-poke operant paradigm for chow or sucrose pellets. To avoid confounding factors linked to food restriction/deprivation experience, mice were always provided with food ad libitum. Although less MOR-/- than wild-type mice initiated operant behaviour, under a fixed ratio-1 (FR-1) reinforcement schedule the two genotypes showed similar patterns of food-driven nose-poking, indicating preserved cognitive abilities in MOR-deficient mice. However, during FR-3 and progressive ratio (PR) reinforcement experiments, MOR-/- mice showed lower levels of nose-poking for either chow or sucrose pellets than wild-type mice, indicating a crucial role for the MOR pathway in the motivational properties of food intake. Moreover, under the PR reinforcement schedule mice nose-poking for sucrose pellets showed higher genotype-independent breakpoint levels than mice working for chow pellets, indicating that the MOR pathway is not essential for hedonic processing of palatable food intake. Finally, MOR-/- mice did not differ from wild-type mice in the rate of operant responding extinction, further supporting the notion of unaltered cognitive abilities in the MOR-deficient mice. The present findings strongly indicate that the MOR pathway mediates the motivational properties of food intake, but it is not essential for hedonic processing of ingestive behaviour

CRF1 receptor-deficiency increases cocaine reward

International audienc

High frequency stimulation of the subthalamic nucleus is efficacious in Parkin disease

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is an efficacious symptomatic treatment for Parkinson's disease. We have analysed the genetic status of a series of consecutive parkinsonian patients implanted for STN HFS and compared the outcome of five carrying mutations in the parkin gene with that of the non-parkin group. All patients obtained sustained control of PD symptoms and achieved functional improvement; in the parkin group the UPDRS motor score improved by 56.4%, the levodopa equivalent daily dosage was reduced by 75.5%. Postoperative medications were reduced more in parkin than in non-parkin patients. We confirm that the current inclusion criteria for STN HFS do not exclude patients carrying mutations in the parkin gene; their clinical outcome is comparable to that of the non-parkin grou

Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior.

Corticotropin-releasing factor (CRF) and its family of peptides are critical coordinators of homeostasis whose actions are mediated through their receptors, CRF receptor 1 (CRFR1) and CRFR2, found throughout the CNS and periphery. The phenotypes of mice deficient in either CRFR1 or CRFR2 demonstrate the critical role these receptors play. CRFR1-mutant mice have an impaired stress response and display decreased anxiety-like behavior, whereas CRFR2-mutant mice are hypersensitive to stress and display increased anxiety-like behavior. To further elucidate the roles of both CRF receptors and determine their interaction in behaviors, we have generated mice deficient in both CRFR1 and CRFR2. The behavioral phenotype of these mice demonstrates a novel role of the mother's genotype on development of pup anxiety. We have found that although the female double-mutant mice display anxiolytic-like behavior, the male double-mutant mice show significantly more anxiety-like behavior compared with the females. We have also determined that the dam's CRFR2 genotype affects the anxiety-like behavior of the male mice, such that a pup born to a heterozygous or mutant dam displays significantly more anxiety-like behavior regardless of that pup's genotype. Double-mutant mice also display an even greater impairment of their hypothalamic-pituitary-adrenal axis response to stress than that of the CRFR1-mutant mice. CRF mRNA levels are elevated in CRFR1- and double-mutant mice, and urocortin III and vasopressin mRNA levels are increased in CRFR2- and double-mutant mice. These results indicate that both CRFR1 and CRFR2 have critical roles in gene regulation and the maintenance of homeostasis in response to stress

Lack of reward and locomotor stimulation induced by heroin in mu-opioid receptor-deficient mice.

The micro-opioid receptor is the main substrate mediating opiate reward. Multiple micro-opioid receptor subtypes have been postulated to underlie opiate actions. Animals treated with antisense oligonucleotides targeting specific micro-opioid receptor exons show differential sensitivity to morphine versus heroin. The present work examined the rewarding and locomotor activating effects of heroin in mutant mice with a disrupted exon 2 of the micro-opioid receptor. Heroin (1-3 mg/kg) produced significant place preferences and stimulated locomotor activity in wild-type mice, whereas it had no effect in micro-opioid receptor-deficient mice. In contrast, treatment with cocaine (10-30 mg/kg) produced comparable place preferences and locomotor activation in both wild-type and micro-opioid receptor-deficient mice, thus providing evidence that the mutant mice are able to show drug-induced effects in the two behavioral paradigms used here. These results support an essential role for the micro-opioid receptor in the rewarding and locomotor activating effects of heroin