Philippe Huguelet

Increased methylation of glucocorticoid receptor gene ( NR3C1 ) in adults with a history of childhood maltreatment: a link with the severity and type of trauma

Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic–pituitary–adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1F NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10−8, 5.18 × 10−7 and 1.25 × 10−9, respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology.

Toward an Integration of Spirituality and Religiousness Into the Psychosocial Dimension of Schizophrenia

OBJECTIVE Spirituality and religiousness have been shown to be highly prevalent among patients with schizophrenia. However, clinicians are rarely aware of the importance of religion and understand little of the value or difficulties it presents to treatment. This study aimed to assess the role of religion as a mediating variable in the process of coping with psychotic illness. METHOD Semistructured interviews about religious coping were conducted with a sample of 115 outpatients with psychotic illness. RESULTS For some patients, religion instilled hope, purpose, and meaning in their lives (71%), whereas for others, it induced spiritual despair (14%). Patients also reported that religion lessened (54%) or increased (10%) psychotic and general symptoms. Religion was also reported to increase social integration (28%) or social isolation (3%). It may reduce (33%) or increase (10%) the risk of suicide attempts, reduce (14%) or increase (3%) substance use, and foster adherence to (16%) or be in opposition to (15%) psychiatric treatment. CONCLUSIONS Our results highlight the clinical significance of religion in the care of patients with schizophrenia. Religion is neither a strictly personal matter nor a strictly cultural one. Spirituality should be integrated into the psychosocial dimension of care. Our results suggest that the complexity of the relationship between religion and illness requires a highly sensitive approach to each unique story.

The assessment of spirituality and religiousness in schizophrenia.

To assess religious coping in schizophrenia, we developed and tested a clinical grid, as no validated questionnaire exists for this population. One hundred fifteen outpatients were interviewed. Results obtained by 2 clinicians were compared. Religion was central in the lives of 45% of patients, 60% used religion extensively to cope with their illness. Religion is a multifaceted construct. Principal component analysis elicited 4 factors: subjective dimension, collective dimension, synergy with psychiatric treatment, and ease of talking about religion with psychiatrist. Different associations were found between these factors and psychopathology, substance abuse, and psychosocial adaptation. The high prevalence of spirituality and religious coping clearly indicates the necessity of addressing spirituality in patient care. Our clinical grid is suitable for this purpose. It proved its applicability to a broad diversity of religious beliefs, even pathological ones. Interjudge reliability and construct validity were high and specific training is not required.

Cyclic AMP-mediated signaling components are upregulated in the prefrontal cortex of depressed suicide victims.

The components of cyclic AMP signaling cascade (catalytic (Calpha) subunit of cyclic AMP-dependent protein kinase (PKA) and cyclic AMP response element binding protein (CREB)) were quantitated by Western blotting in the prefrontal cortex of depressed suicide victims (n=23) and their matched controls (n=14). There was a significant increase in the levels of CREB, both in total (tCREB; 121+/-8% (mean+/-S.E.M.), P<0.02) and phosphorylated (pCREB; 128+/-9%, P<0.01) forms, but not in PKA Calpha levels (109+/-9%, ns), in brains of depressed suicides compared to those in control subjects. The increases in CREB were specifically observed in antidepressant drug-free subjects (tCREB: 137+/-11%, P<0.01; pCREB: 136+/-12%, P<0.02; n=9), but not in the antidepressant-treated subjects (tCREB: 108+/-18%, ns; pCREB: 111+/-17%, ns; n=8). There were significant correlations between the levels of PKA and those of tCREB and pCREB in the prefrontal cortex of depressed suicides. These results indicate that the components of cyclic AMP signaling are upregulated in a coordinated manner in brains of depressed suicides and that this alteration is not related to antidepressant treatment.

Spirituality and religiousness as predictive factors of outcome in schizophrenia and schizo-affective disorders

Spirituality and religiousness have been shown to be highly prevalent in patients with schizophrenia. This study assesses the predictive value of helpful vs. harmful use of religion to cope with schizophrenia or schizo-affective disorder at 3 years. From an initial cohort of 115 outpatients, 80% were reassessed for positive, negative and general symptoms, clinical global impression, social adaptation and quality of life. For patients with helpful religion at baseline, the importance of spirituality was predictive of fewer negative symptoms, better clinical global impression, social functioning and quality of life. The frequencies of religious practices in community and support from religious community had no effect on outcome. For patients with harmful religion at baseline, no relationships were elicited. This result may be due to sample size. Indeed, helpful spiritual/religious coping concerns 83% of patients, whereas harmful spiritual/religious coping concerns only 14% of patients. Our study shows that helpful use of spirituality is predictive of a better outcome. Spirituality may facilitate recovery by providing resources for coping with symptoms. In some cases, however, spirituality and religiousness are a source of suffering. Helpful vs. harmful spiritual/religious coping appears to be of clinical significance.

A Randomized Trial of Spiritual Assessment of Outpatients With Schizophrenia: Patients' and Clinicians' Experience

OBJECTIVE Recovery-oriented care for patients with schizophrenia involves consideration of cultural issues, such as religion and spirituality. However, there is evidence that psychiatrists rarely address such topics. This study examined acceptance of a spiritual assessment by patients and clinicians, suggestions for treatment that arose from the assessment, and patient outcomes--in terms of treatment compliance and satisfaction with care (as measured by treatment alliance). METHODS Outpatients with psychosis were randomly assigned to two groups: an intervention group that received traditional treatment and a religious and spiritual assessment (N=40) and a control group that received only traditional treatment (N=38). Eight psychiatrists were trained to administer the assessment to their established and stable patients. After each administration, the psychiatrist attended a supervision session with a psychiatrist and a psychologist of religion. Baseline and three-month data were collected. RESULTS The spiritual assessment was well accepted by patients. During supervision, psychiatrists reported potential clinical uses for the assessment information for 67% of patients. No between-group differences in medication adherence and satisfaction with care were found at three months, although patients in the intervention group had significantly better appointment attendance during the follow-up period. Their interest in discussing religion and spirituality with their psychiatrists remained high. The process was not as well accepted by psychiatrists. CONCLUSIONS Spiritual assessment can raise important clinical issues in the treatment of patients with chronic schizophrenia. Cultural factors, such as religion and spirituality, should be considered early in clinical training, because many clinicians are not at ease addressing such topics with patients.

Regulation of GRK 2 and 6, β-arrestin-2 and associated proteins in the prefrontal cortex of drug-free and antidepressant drug-treated subjects with major depression

G protein-coupled receptor kinases (GRKs) and beta-arrestin-2 play a crucial role in the regulation of neurotransmitter receptors in brain. In this study, GRK 2, GRK 6, beta-arrestin-2 and associated proteins (Gbeta proteins and protein phosphatase (PP)-2A) were quantitated in parallel (immunodensity with specific antibodies) in brains of depressed subjects (drug-free and antidepressant-treated) to investigate the effect of major depression and antidepressant drugs on these receptor regulatory proteins. Specimens of the prefrontal cortex (Brodmanns area 9) were collected from 19 suicide and non-suicide depressed subjects and 13 control subjects. In drug-free (n=9), but not in antidepressant-treated (n=10), depressed subjects an increase in the density of membrane-associated GRK 2 (30%, n=9, P=0.005) was found compared with that in sex-, age-, and PMD-matched controls. Comparison between drug-free and antidepressant-treated depressed subjects showed that GRK 2 was reduced in membrane (39%, n=10, P=0.008) and cytosolic (44%, n=10, P=0.09) preparations after antidepressant drug treatment. In contrast, membrane-associated GRK 6 (drug-free and antidepressant-treated depressed subjects) was found unchanged when compared with that in matched controls. Similarly, the densities of beta-arrestin-2, PP-2A, and Gbeta proteins were not significantly different from those in matched controls. There was a positive correlation between the immunodensities of GRK 2 and beta-arrestin-2 in membrane preparations (r=0.48, n=19, P=0.04), suggesting that both proteins are regulated in a coordinated manner in brains of depressed subjects. The results of this study indicate that major depression is associated with upregulation of brain GRK 2, but not GRK 6, and that antidepressant drug treatment appears to induce downregulation of GRK 2 protein.

Rare Genotype Combination of the Serotonin Transporter Gene Associated With Treatment Response in Severe Personality Disorder

The insertion deletion (ins/del) polymorphism of the serotonin transporter gene (5‐HTTLPR) has been associated with several psychiatric phenotypes and antidepressants response. We investigated, in a large cohort of 5,608 controls and subjects suffering from various psychiatric disorders, the frequency of haplotypes and corresponding genotypes combining the 5‐HTTLPR and the other serotonin transporter promoter functional variant (rs25531). We showed that rs25531 lies 18 bp 5′ to the site where the 43 bp (and not 44 bp as previously described) ins/del defines the 14‐ and 16‐repeat alleles. These polymorphisms should therefore be considered as four alleles instead of a triallelic unique locus. The very rare G‐14/G‐16 genotype was carried on by only three subjects. These are women with a history of suicide attempt with a psychiatric history strongly suggesting a borderline personality disorder. Two of them have shown a non‐response to serotoninergic antidepressant. Interestingly, in one of them was observed a spectacular response after the introduction of bupropion. The genotyping droved our therapeutic approach, by preferring a dopaminergic over a serotoninergic agent. This study highlights the usefulness of studying very rare clinical cases as well as rare variants, in order to deal with the biological heterogeneity of spectral disorders.

Mindfulness skills in borderline personality disorder patients during dialectical behavior therapy: preliminary results.

Objective. One of the components of dialectical behavior therapy (DBT) is the use of mindfulness skills as a core component of treatment for subjects with borderline personality disorder (BPD). In this study, we investigated changes in and correlates of mindfulness skills over a 1-year follow-up including a 4-week session of intensive DBT followed by 10 months of standard DBT. Methods. Fifty-two BPD subjects were assessed several times using the Kentucky Inventory of Mindfulness Skills (KIMS) which describes mindfulness in four discrete dimensions: observing (Obs), describing (Des), acting with awareness (AwA) and accepting without judgment (AwJ). Results. AwJ was the only dimension that increased significantly over time after adjustment for potential confounding factors (β = 0.24; P = 0.0002). Increases in AwJ correlated with improvement in BPD symptoms. Conclusions. This study highlights the usefulness of investigating changes in mindfulness dimensions during DBT. AwJ is a possible mechanism for positive change. Encouraging this skill should lead to a more adaptive response to problematic situations and counteract impulsive and problematic behaviors. The lack of specific control groups means that these findings are preliminary and replication is required.

Nicotine gum treatment before smoking cessation: a randomized trial.

BACKGROUND New ways of improving the efficacy of nicotine therapy need to be explored. We tested whether starting nicotine polacrilex gum treatment 4 weeks before the quit date improved smoking abstinence rates compared with starting treatment on the quit date. METHODS An open randomized trial of 314 daily smokers (mean, 23.7 cigarettes/d) enrolled through the Internet and by physicians in Switzerland from November 2005 to January 2007. In the precessation treatment group, participants received nicotine polacrilex gum (4 mg, unflavored) by mail for 4 weeks before and 8 weeks after their target quit date, and they were instructed to decrease their cigarette consumption by half before quitting. In the usual care group, participants received the same nicotine gum for 8 weeks after their quit date and were instructed to quit abruptly. Instructions were limited to a booklet sent by mail and access to a smoking cessation Web site. Results are expressed as self-reported abstinence rates at the end of treatment and as biochemically verified smoking abstinence (cotinine plus carbon monoxide) after 12 months. RESULTS Eight weeks after the target quit date, self-reported 4-week abstinence rates were 41.6% in the precessation treatment group and 44.4% in the usual care group (P = .61). One year after the target quit date, biochemically verified 4-week smoking abstinence rates were 20.8% in the precessation treatment group and 19.4% in the usual care group (P = .76). CONCLUSION Starting nicotine gum treatment 4 weeks before the target quit date was no more effective than starting treatment on the quit date.