Repressive Epigenetic Changes at the Mglu2 Promoter in Frontal Cortex of 5-HT2A Knockout Mice.

Repressive Epigenetic Changes at the Mglu2 Promoter in Frontal Cortex of 5-HT2A Knockout Mice.

Mol Pharmacol. 2013 Mar 18;
Kurita M, Moreno JL, Holloway T, Kozlenkov A, Mocci G, Garcia-Bea A, Hanks JB, Neve R, Nestler EJ, Russo SJ, Gonzalez-Maeso J

Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders such as schizophrenia, depression and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT2A-KO mice. Disruption of 5-HT2A receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac), and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter-epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor whose promoter activity was positively regulated by the 5-HT2A receptor agonist TCB-2, binds less to the mGlu2 promoter in frontal cortex of 5-HT2A-KO as compared to wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of Flag-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT2A receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex. HubMed – depression


Persistent sleep disturbance is associated with treatment response in adolescents with depression.

Aust N Z J Psychiatry. 2013 Mar 18;
Manglick M, Rajaratnam SM, Taffe J, Tonge B, Melvin G

Background:Sleep disturbances are highly prevalent in adolescents with depressive disorders. To date there is limited evidence of the extent to which sleep disturbances are associated with treatment response in adolescents. This study aimed to examine the extent to which self-reported sleep disturbances are associated with treatment response in adolescents with depression.Method:Sleep data were gathered from a sample of 166 adolescents (aged 12-18 years) with a diagnosis of a DSM-IV depressive disorder who underwent 3 months of treatment (psychosocial and/or pharmacotherapy (sertraline)) in community-based research programs. The subjective report of sleep disturbance within depressive disorders was assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children at three time points: pre-treatment, post-treatment and 6-month follow-up.Results:Sixty-nine percent of participants had a sleep disturbance pre-treatment and approximately 75% of these participants had threshold symptoms. Threshold sleep disturbances that persisted from pre- to post-treatment assessments were positively associated with depression at the 6-month follow-up. An ordered logistic regression model controlling for gender, treatment group and comorbid anxiety estimated a 70% risk of depression or partial remission for those with persistent sleep disturbance. Treatment group, anxiety and gender generally had no significant effect on the relationship between sleep and depression.Conclusion:Sleep disturbances were highly related to depressive state and were associated with poorer treatment response in adolescents with depression. These results provide a rationale for further exploration of sleep-related treatments for adolescents with depression. Knowledge of patient-reported persistent sleep disturbances can help clinicians to predict treatment outcomes and may direct them to augment treatment or focus on sleep-related treatment strategies. HubMed – depression


Treatment Course With Antidepressant Therapy in Late-Life Depression.

Am J Psychiatry. 2012 Nov 1; 169(11): 1185-1193
Sheline YI, Disabato BM, Hranilovich J, Morris C, D’Angelo G, Pieper C, Toffanin T, Taylor WD, Macfall JR, Wilkins C, Barch DM, Welsh-Bohmer KA, Steffens DC, Krishnan RR, Doraiswamy PM

OBJECTIVE In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial. METHOD In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antidepressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time. RESULTS Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyperintensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not. CONCLUSIONS These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response. HubMed – depression


Psychopathology in Adolescent Offspring of Parents With Panic Disorder, Major Depression, or Both: A 10-Year Follow-Up.

Am J Psychiatry. 2012 Nov 1; 169(11): 1175-1184
Hirshfeld-Becker DR, Micco JA, Henin A, Petty C, Faraone SV, Mazursky H, Bruett L, Rosenbaum JF, Biederman J

OBJECTIVE The authors examined the specificity and course of psychiatric disorders from early childhood through adolescence in offspring of parents with confirmed panic disorder and major depressive disorder. METHOD The authors examined rates of psychiatric disorders at 10-year-follow-up (mean age, 14 years) in four groups: offspring of referred parents with panic and depression (N=137), offspring of referred parents with panic without depression (N=26), offspring of referred parents with depression without panic (N=48), and offspring of nonreferred parents with neither disorder (N=80). Follow-up assessments relied on structured interviews with the adolescents and their mothers; diagnoses were rated present if endorsed by either. RESULTS Parental panic disorder, independently of parental depression, predicted lifetime rates in offspring of multiple anxiety disorders, panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Parental depression independently predicted offspring bipolar, drug use, and disruptive behavior disorders. Parental panic and depression interacted to predict specific phobia and major depressive disorder. Phobias were elevated in all at-risk groups, and depression was elevated in both offspring groups of parents with depression (with or without panic disorder), with the highest rates in the offspring of parents with depression only. Parental depression independently predicted new onset of depression, parental panic disorder independently predicted new onset of social phobia, and the two interacted to predict new onset of specific phobia and generalized anxiety disorder. CONCLUSIONS At-risk offspring continue to develop new disorders as they progress through adolescence. These results support the need to screen and monitor the offspring of adults presenting for treatment of panic disorder or major depressive disorder. HubMed – depression