Gen Shinozaki

Sexual Abuse and Lifetime Diagnosis of Psychiatric Disorders: Systematic Review and Meta-analysis

OBJECTIVEnTo systematically assess the evidence for an association between sexual abuse and a lifetime diagnosis of psychiatric disorders.nnnPATIENTS AND METHODSnWe performed a comprehensive search (from January 1980-December 2008, all age groups, any language, any population) of 9 databases: MEDLINE, EMBASE, CINAHL, Current Contents, PsycINFO, ACP Journal Club, CCTR, CDSR, and DARE. Controlled vocabulary supplemented with keywords was used to define the concept areas of sexual abuse and psychiatric disorders and was limited to epidemiological studies. Six independent reviewers extracted descriptive, quality, and outcome data from eligible longitudinal studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled across studies by using the random-effects model. The I(2) statistic was used to assess heterogeneity.nnnRESULTSnThe search yielded 37 eligible studies, 17 case-control and 20 cohort, with 3,162,318 participants. There was a statistically significant association between sexual abuse and a lifetime diagnosis of anxiety disorder (OR, 3.09; 95% CI, 2.43-3.94), depression (OR, 2.66; 95% CI, 2.14-3.30), eating disorders (OR, 2.72; 95% CI, 2.04-3.63), posttraumatic stress disorder (OR, 2.34; 95% CI, 1.59-3.43), sleep disorders (OR, 16.17; 95% CI, 2.06-126.76), and suicide attempts (OR, 4.14; 95% CI, 2.98-5.76). Associations persisted regardless of the victims sex or the age at which abuse occurred. There was no statistically significant association between sexual abuse and a diagnosis of schizophrenia or somatoform disorders. No longitudinal studies that assessed bipolar disorder or obsessive-compulsive disorder were found. Associations between sexual abuse and depression, eating disorders, and posttraumatic stress disorder were strengthened by a history of rape.nnnCONCLUSIONnA history of sexual abuse is associated with an increased risk of a lifetime diagnosis of multiple psychiatric disorders.

The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes

To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcomes.

Which patient will feel down, which will be happy? The need to study the genetic disposition of emotional states

PurposeIn quality-of-life (QL) research, the genetic susceptibility of negative and positive emotions is frequently ignored, taken for granted, or treated as noise. The objectives are to describe: (1) the major findings of studies addressing the heritable and environmental causes of variation in negative and positive emotional states and (2) the major biological pathways of and genetic variants involved in these emotional states.MethodsLiterature overview.ResultsThe heritability estimates for anxiety and depression are 30–40%. Related traits as neuroticism and loneliness are also highly heritable. The hypothalamo–pituitary–adrenal axis is the ‘final common pathway’ for most depressive symptoms. The many findings of investigated genes are promising but not definitive. Heritability estimates of positive emotional states range between 40 and 50%. Life satisfaction and mental health share common genetic factors with optimism and self-esteem. The prefrontal cortex is a candidate brain area for positive emotional states. Biological and genetic research into positive emotional states is scarce.ConclusionGenetically informative studies may provide insights into a wide variety of complex questions that traditional QL studies cannot deliver. This insight in turn will help us to design more effective supportive programs that could moderate the outcomes of genetically based predispositions.

New Developments in the Genetics of Bipolar Disorder

The last several years have been breakthrough ones in bipolar disorder (BPD) genetics, as the field has identified robust risk variants for the first time. Leading the way have been genome-wide association studies (GWAS) that have assessed common genetic markers across very large groups of patients and controls. These have resulted in findings in genes including ANK3, CACNA1C, SYNE1, ODZ4, and TRANK1. Additional studies have begun to examine the biology of these genes and how risk variants influence aspects of brain and behavior that underlie BPD. For example, carriers of the CACNA1C risk variant have been found to exhibit hippocampal and anterior cingulate dysfunction during episodic memory recall. This work has shed additional light on the relationship of bipolar susceptibility variants to other disorders, particularly schizophrenia. Even larger BPD GWAS are expected with samples now amassed of 21,035 cases and 28,758 controls. Studies have examined the pharmacogenomics of BPD with studies of lithium response, yielding high profile results that remain to be confirmed. The next frontier in the field is the identification of rare bipolar susceptibility variants through large-scale DNA sequencing. While only a couple of papers have been published to date, many studies are underway. The Bipolar Sequencing Consortium has been formed to bring together all of the groups working in this area, and to perform meta-analyses of the data generated. The consortium, with 13 member groups, now has exome data on ~3,500 cases and ~5,000 controls, and on ~162 families. The focus will likely shift within several years from exome data to whole genome data as costs of obtaining such data continue to drop. Gene-mapping studies are now providing clear results that provide insights into the pathophysiology of the disorder. Sequencing studies should extend this process further. Findings could eventually set the stage for rational therapeutic development.

Treatment outcomes of depression: the pharmacogenomic research network antidepressant medication pharmacogenomic study.

Background The effectiveness of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD) is controversial. Aims The clinical outcomes of subjects with nonpsychotic MDD were reported and compared with the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study outcomes to provide guidance on the effectiveness of SSRIs. Methods Subjects were treated with citalopram/escitalopram for up to 8 weeks. Depression was measured using the Quick Inventory of Depressive Symptomatology—Clinician Rated (QIDS-C16) and the 17-item Hamilton Depression Rating Scale. Results The group of subjects with at least 1 follow-up visit had a remission (QIDS-C16 ⩽ 5) rate of 45.8% as well as a response (50% reduction in QIDS-C16) rate of 64.8%, and 79.9% achieved an improvement of 5 points or higher in QIDS-C16 score. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study subjects were more likely to achieve a response than STAR*D study subjects. After adjustment for demographic factors, the response rates were not significantly different. When reporting the adverse effect burden, 60.5% of the subjects reported no impairment, 31.7% reported a minimal-to-mild impairment, and 7.8% reported a moderate-to-severe burden at the 4-week visit. Conclusions Patients contemplating initiating an SSRI to treat their MDD can anticipate a high probability of symptom improvement (79.9%) with a low probability that their symptoms will become worse. Patients with lower baseline severity have a higher probability of achieving remission. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study replicates many findings of the first phase of the STAR*D study after controlling for the differences between the studies.

State dependent gene-environment interaction: Serotonin transporter gene-child abuse interaction associated with suicide attempt history among depressed psychiatric inpatients

BACKGROUNDnThe serotonin transporter gene polymorphism (5HTTLPR) and child abuse history have been associated with an increased suicide risk for general population, but such association is not clear among psychiatric depressed inpatients.nnnMETHODSnA chart review identified 422 depressed inpatients genotyped for 5HTTLPR. Child abuse and suicide attempt history were recorded. The relationship between 5HTTLPR, child abuse, and suicide attempts were analyzed.nnnRESULTSnThere was a significant relationship between 5HTTLPR and history of suicide attempt (the long/long versus the short carriers, 47.9% versus 31.8%, p=0.0015). There was also a significant main effect from child abuse history (abused versus not abused, 45.1% versus 28.6%, p=0.0001). The likelihood ratio test showed a significant result for the l/l genotype group with child abuse history (odds ratio 4.11, χ2 = 23.5, p<0.0001). No significant result was obtained from other groups.nnnLIMITATIONSnThis is a retrospective study based on chart review. Replication with more standardized research setting for measurements of child abuse history and suicide attempt history is needed. The rs25531 variant among a long allele (long-A and long-G) of 5HTTLPR was not genotyped.nnnCONCLUSIONSnIn addition to the direct effect from 5HTTLPR and child abuse history, an interaction between the 5HTTLPR gene and child abuse history influenced psychiatric profiles of depressed inpatients. Contrary to the widely recognized reactivity associated with the short allele, our patients with the l/l genotype and child abuse history showed significantly severer psychiatric pathology than short carriers with child abuse history.

Pharmacogenomic Testing in a Tertiary Care Outpatient Psychosomatic Medicine Practice

BACKGROUNDnPharmacogenomic testing (PGT) has applicability in psychosomatic medicine (PM) practice where medical comorbidity and polypharmacy present particularly difficult challenges of drug-drug and drug-disease interactions. No guidelines currently exist for cost-effective use of PGT in PM practice.nnnOBJECTIVEnThe authors tested the hypothesis that naturalistically observed PGT ordering patterns and clinical data on test utility derived from a PM practice where PGT is readily available may inform the development of clinical guidelines for cost-effective use of PGT.nnnMETHODnTwo sets of data were collected from an outpatient PM practice staffed by seven PM-certified psychiatrists. Psychiatrists were surveyed regarding their indications for ordering PGT. Medical records of patients seen in the PM practice during 2008 were reviewed. Patients who had PGT were compared with two sets of case controls who were not tested, one matched by demographics, the other by ordering psychiatrist. Psychiatrists ordering indications were compared with clinical data derived from the case-control analyses.nnnRESULTSnPsychiatrists listed treatment-resistance as the most common reason for PGT, ahead of intolerance to previous medications. Tested patients differed from controls on measures of both clinical severity and treatment-resistance, including higher self-reported anxiety and depression levels, greater likelihood of family history of mood or anxiety disorders, and larger numbers of prior antidepressant, mood stabilizer, and antipsychotic medication trials.nnnCONCLUSIONnOrdering guidelines that emphasize markers of clinical severity and early indicators of treatment-resistance may provide a useful rationale for PGT in outpatient PM practice. Prospective investigations of this proposition are warranted.

Serotonin transporter gene promotor polymorphism (5-HTTLPR) associations with number of psychotropic medication trials in a tertiary care outpatient psychiatric consultation practice.

OBJECTIVEnThe authors tested the hypothesis that the short allele of 5-HTTLPR is associated with number of psychotropic medication trials as a measure of treatment-resistance or intolerance in psychosomatic medicine (PM) outpatients.nnnMETHODSnReview of Mayo Clinic PM outpatient 2008 records identified 44 (20.6%) who had 5-HTTLPR genotype tests. A univariate analysis screened for factors that could account for number of medication trials. Logistic regression then determined degree of association between 5-HTTLPR genotype category and number of pharmacological trials.nnnRESULTSnUnivariate analysis revealed significant differences across the ordinal genotype spectrum long/long, short/long, short/short in mean number of overall psychotropic medication trials (8.9, 14.8, 18.0, P = 0.002), mean number of antidepressant trials (4.3, 7.2, 8.1, P = 0.018), mean number of mood stabilizer trials (0.8, 1.9, 2.3, P = 0.008), percent living alone (7%, 25%, 50%, P = 0.020), reported family history of depression (93%, 65%, 40%, P = 0.006), and reported family history of chemical dependency treatment (50%, 35%, 10%, P = 0.050). There were trends for differences in consultation reason for unexplained symptoms (14%, 25%, 50%, P = 0.063), and diagnoses of somatoform disorder (7%, 30%, 40%, P = 0.060), and generalized anxiety disorder (43%, 65%, 80%, P = 0.064). After controlling for other differences, presence of the short allele remained associated with number of psychotropic medication trials (OR 4.779, 95% CI 2.263-6.771, P = 0.004), and number of antidepressant trials (OR 1.591, 95% CI 1.072-2.762, P = 0.019).nnnCONCLUSIONn5-HTTLPR testing may identify PM outpatients at higher relative risk for pharmacotherapy treatment non-response or intolerance who may benefit from alternative or augmentative medication recommendations or non-pharmacological interventions.

HTR2A gene–child abuse interaction and association with a history of suicide attempt among Caucasian depressed psychiatric inpatients

BACKGROUNDnThe serotonin transporter gene polymorphism (5HTTLPR) has been associated with vulnerability for depression after exposure to stressful life event as well as with difference in treatment response to SSRI. Although the A/A genotype of the serotonin receptor SNP (rs7997012) was associated with better citalopram response than the G/G in the STAR⁎D sample, the effects of this SNP in the moderation of child abuse history on the characteristics of mental illnesses are not well understood. We examined if there are similar gene-environment interaction with the SNP.nnnMETHODSnRetrospective chart review of 250 Caucasian depressed psychiatric inpatients, who had genotype for rs7997012. Subjects with each genotype were subcategorized into 2 groups with/without history of child abuse. The history of suicide attempts of each group was compared.nnnRESULTSnA trend for an interaction was found between the HTR2A genotype and child abuse history influencing the prevalence of suicide attempts. Although each genotype did not show significant difference in the risk of suicide attempt when there was no abuse history, the A carriers (A/A+A/G) showed significantly higher rate of suicide attempt compared to the G/G when there is a history of child abuse (48.4% versus 22.7% respectively, p=0.0050). The likelihood ratio test from the logistic model showed a trend for an interaction between the A/A genotype and abuse history (Odds Ratio 2.10, χ(2)=2.49, p=0.11).nnnLIMITATIONSnRetrospective study design and small sample size with borderline significance.nnnCONCLUSIONSnOur findings showed a potential interaction between the HTR2A gene and stressful life events.

A new interaction between SLC6A4 variation and child abuse is associated with resting heart rate

Background: The short form of the indel promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) and a history of child abuse have been reported to be associated with an increased risk for the development of depression. A child abuse history has also been associated with more rapid heart rate reactions. Methods: A retrospective chart review identified 282 patients with major depression who had been hospitalized and genotyped for the 5HTTLPR polymorphism. A subgroup of 185 females of European ancestry was also identified and analyzed. While hospitalized, heart rate was measured. Child abuse history was documented during the diagnostic evaluation. Analyses of the relationship between 5HTTLPR genotype, history of child abuse, and admission heart rate were conducted. Results: No main effect on heart rate from the 5HTTLPR genotype or a child abuse history was demonstrated for the entire sample or the subgroup of female patients. However, a genotype‐by‐abuse interaction was associated with resting heart rate on admission to the hospital (P<.05). Depressed patients, who were homozygous for the long allele and who had been abused, had a heart rate on hospital admission, which was statistically higher than patients with the same genotype but who had not been abused. These findings were consistent both for the 282 patients (7.2u2009bpm higher) as well as for the subgroup of 185 female patients of European ancestry (9.6u2009bpm higher). Conclusions: A 5HTTLPR genotype interaction of elevated heart rate with a history of child abuse was demonstrated in depressed psychiatric inpatients. Depression and Anxiety 28:227‐233, 2011.u2003u2003© 2010 Wiley‐Liss, Inc.