COMT Val158Met Polymorphism and Symptom Improvement Following a Cognitively Focused Intervention for Irritable Bowel Syndrome.

BACKGROUND: Our nurse-delivered comprehensive self-management (CSM) program, a cognitive behavioral therapy intervention, is effective in reducing gastrointestinal and psychological distress symptoms in patients with irritable bowel syndrome (IBS). Findings from non-IBS studies indicate that the catechol-O-methyltransferase (COMT) Val158Met polymorphism may moderate the efficacy of cognitive behavioral therapy. It is unknown whether this COMT polymorphism is associated with symptom improvements in patients with IBS. OBJECTIVE: We tested whether this COMT Val158Met polymorphism influences the efficacy of our 2-month CSM intervention. METHODS: We analyzed data from two published randomized controlled trials of CSM. The combined European American sample included 149 women and 23 men with IBS (CSM, n = 111; usual care [UC], n = 61). The primary outcomes were daily reports of abdominal pain, depression, anxiety, and feeling stressed measured 3 and 6 months after randomization. Secondary outcomes were additional daily symptoms, retrospective psychological distress, IBS quality of life, and cognitive beliefs about IBS. The interaction between COMT Val158Met polymorphism and treatment group (CSM vs. UC) in a generalized estimating equation model tested the main objective. RESULTS: At 3 months, participants with at least one Val allele benefited more from CSM than did those with the Met/Met genotype (p = .01 for anxiety and feeling stressed, and p < .16 for abdominal pain and depression). The moderating effect of genotype was weaker at 6 months. DISCUSSION: Persons with at least one Val allele may benefit more from CSM than those homozygous for the Met allele. Future studies with larger and more racially diverse samples are needed to confirm these findings. RCT REGISTRATION: Parent studies were registered at ClinicalTrials.gov (NCT00167635 and NCT00907790).

Symptom profiles and inflammatory markers in moderate to severe COPD.

BACKGROUND: Physical and psychological symptoms are the hallmark of patients' subjective perception of their illness. The purpose of this analysis was to determine if patients with COPD have distinctive symptom profiles and to examine the association of symptom profiles with systemic biomarkers of inflammation. METHODS: We conducted latent class analyses of three physical (dyspnea, fatigue, and pain) and two psychological symptoms (depression and anxiety) in 302 patients with moderate to severe COPD using baseline data from a longitudinal observational study of depression in COPD. Systemic inflammatory markers included IL1, IL8, IL10, IL12, IL13, INF, GM-CSF, TNF-α (levels >75thcentile was considered high); and CRP (levels >3 mg/L was considered high). Multinominal logistic regression models were used to examine the association between symptom classes and inflammation while adjusting for key socio-demographic and disease characteristics. RESULTS: We found that a 4-class model best fit the data: 1) low physical and psychological symptoms (26%, Low-Phys/Low-Psych), 2) low physical but moderate psychological symptoms (18%, Low-Phys/Mod Psych), 3) high physical but moderate psychological symptoms (25%, High-Phys/Mod Psych), and 4) high physical and psychological symptoms (30%, High-Phys/High Psych). Unadjusted analyses showed associations between symptom class with high levels of IL7, IL-8 (p ≤ .10) and CRP (p < .01). In the adjusted model, those with a high CRP level were less likely to be in the High-Phys/Mod-Psych class compared to the Low-Phys/Low-Psych (OR: 0.41, 95%CI 0.19, 0.90) and Low-Phys/Mod-Psych classes (OR: 0.35, 95%CI 0.16, 0.78); elevated CRP was associated with in increased odds of being in the High-Phys/High-Psych compared to the High-Phys/Mod-Psych class (OR: 2.22, 95%CI 1.08, 4.58). Younger age, having at least a college education, oxygen use and depression history were more prominent predictors of membership in the higher symptom classes. CONCLUSIONS: Patients with COPD can be classified into four distinct symptom classes based on five commonly co-occurring physical and psychological symptoms. Systemic biomarkers of inflammation were not associated with symptom class. Additional work to test the reliability of these symptom classes, their biological drivers and their validity for prognostication and tailoring therapy in larger and more diverse samples is needed. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01074515 .

Poststroke fatigue: hints to a biological mechanism.

BACKGROUND: Poststroke fatigue (PSF) is common, but the biological basis of this fatigue is unknown. We explored the possibility that PSF is related to systemic inflammation by investigating polymorphisms in 2 genes that affect the immune response. METHODS: In a substudy of a larger trial that evaluated the role of the immune response on stroke outcome, fatigue was assessed at 30, 90, 180, and 365 days after ischemic stroke using the Fatigue Assessment Scale. Subjects were genotyped for 3 single nucleotide polymorphisms, one in the interleukin-1 receptor antagonist gene (IL1RN; rs4251961, a T/C substitution) and two in the in toll-like receptor-4 (TLR4) gene (1063 A/G [Asp299Gly] rs4986790 and 1363 C/T [Thr399Ile] rs4986791). RESULTS: Of the 39 participants, 22 (56%) endorsed fatigue during the study. The degree of fatigue was remarkably constant over time and independent of stroke outcome. The C allele of the rs4251961 single nucleotide polymorphism (SNP) in IL1RN was associated with self-reported fatigue (P = .03), whereas the cosegregating polymorphisms in TLR4 were associated with lower levels of fatigue (P= .04). CONCLUSIONS: SNPs in 2 genes with opposing effects on inflammatory immune responses were significantly, but differentially, associated with PSF. These findings suggest a direct link between immune signaling dysregulation and PSF.

Epidemiologic Associations Between Inflammatory Bowel Disease and Hodgkin Lymphoma or Multiple Sclerosis.

Background and Aims: Epidemiologic evidence suggests that Hodgkin lymphoma (HL) and multiple sclerosis (MS) share a common set of risk factors with Crohn's disease (CD) and ulcerative colitis (UC). It was hypothesized that such shared risk factors would lead to similar geographic distributions of these 4 diagnoses and their concurrence in identical patients. Methods: All subjects with HL, MS, CD, or UC were identified in the complete Inpatient Standard Analytic File of the Centers for Medicare and Medicaid Services from 2018. In a cross-sectional study, we evaluated whether the frequencies of HL, MS, CD, and UC occurrences among different US states were statistically correlated with each other. In a case-control study, the observed concurrences of each 2 of the 4 diagnoses were compared with their expected frequencies in the overall Medicare population by calculating odds ratios with their 95% confidence intervals. Results: The total Centers for Medicare and Medicaid Services population comprised 6,462,321 unique patients, of whom 8027 presented with HL, 42,934 with MS, 40,623 with CD, and 32,521 with UC. Statistically significant positive correlations (r) with P < .001 were found between HL and MS (r = 0.50), HL and CD (0.46), HL and UC (0.68), MS and CD (0.66), MS and UC (0.72), and CD and UC (0.68). Any inflammatory bowel disease was significantly associated with a diagnosis of concurrent HL (odds ratio: 1.22, 95% confidence interval: 1.01-1.48) or MS (1.35, 1.25-1.46). Conclusion: The epidemiologic associations of inflammatory bowel disease with HL or MS may reflect a common pathway in the etiology or pathogenesis of these diseases.

Response to psychosocial treatment in poststroke depression is associated with serotonin transporter polymorphisms.

BACKGROUND AND PURPOSE: The Living Well With Stroke study has demonstrated effectiveness of a brief psychosocial treatment in reducing depressive symptoms after stroke. The purpose of this analysis was to determine whether key variables associated with prevalence of poststroke depression also predicted treatment response. METHODS: Response to a brief psychosocial/behavioral intervention for poststroke depression was measured with the Hamilton Rating Scale for Depression. Analysis of covariance models tested for interaction of potential predictor variables with treatment group on percent change in Hamilton Rating Scale for Depression from pre- to post-treatment as an outcome. RESULTS: Initial depression severity, hemispheric location, level of social support, age, gender, and antidepressant adherence did not interact with the treatment with respect to percent change in Hamilton Rating Scale for Depression when considered 1 at a time. Participants who carried 1 or 2 s-alleles at the 5-HTTLPR serotonin transporterpolymorphism or 1 or 2 9- or 12-repeats of the STin2 VNTR polymorphism had significantly better response to psychosocial treatment than those with no s-alleles or no 9- or 12-repeats. CONCLUSIONS: Opposite to the effects of antidepressant drug treatment with selective serotonin reuptake inhibitors, the Living Well With Stroke psychotherapy intervention was most effective in 5-HTTLPR s-allele carriers and STin2VNTR 9- or 12-repeat carriers. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov/ct/show/NCT00194454?order_1. Unique identifier: NCT00194454.

Genetics and gastrointestinal symptoms.

Gastrointestinal (GI) symptoms including nausea, vomiting, diarrhea, constipation, abdominal discomfort/pain, and heartburn are ubiquitous and as such are often the focus of nursing interventions. The etiologies of these symptoms include GI pathology (e.g., cancer, inflammation), dietary factors (e.g., lactose intolerance), infection, stress, autonomic nervous system dysregulation, medications, as well as a host of diseases outside the GI tract. This review focuses on a common condition (irritable bowel syndrome [IBS]) that is linked with both bowel pattern and abdominal discomfort/pain symptoms. Family and twin studies give evidence for a role of genetic factors in IBS. Whether genes are directly associated with IBS or influence disease risk indirectly by modulating the response to environmental factors remains unknown at this time. Given the multifactorial nature of IBS, it is unlikely that a single genetic factor is responsible for IBS. In addition, gene-gene (epistatic) interactions are also likely to play a role. Four genes coding for proteins involved in neurotransmission (i.e., the serotonin reuptake transporter [SERT], tryptophan hydroxylase [TPH], alpha2-adrenergic receptor [alpha2-ADR], catechol-o-methyl transferase [COMT]) and their potential relevance to GI symptoms and IBS will be reviewed. Further research using genome-wide association approaches with samples well characterized by ethnicity and standardized symptom subgrouping is needed.

Brief Psychosocial Intervention to Address Poststroke Depression May Also Benefit Fatigue and Sleep-Wake Disturbance.

PURPOSE: This study aimed to determine if brief psychosocial/behavioral therapy directed to reduce poststroke depression would decrease fatigue and improve sleep-wake disturbance. DESIGN: A preplanned secondary data analysis from a completed clinical trial was conducted. METHODS: One hundred participants received usual care, in-person intervention, or telephone intervention. Depression, fatigue, and sleep-wake disturbance were measured at entry, 8 weeks, 21 weeks, and 12 months following the intervention. FINDINGS: Fatigue (within: p = .042, between: p = .394), sleep disturbance (within: p = .024, between: p = .102), and wake disturbance (within: p = .004, between: p = .508) decreased over the 12 months in the intervention groups, but not in the control group. This difference was clinically meaningful for wake disturbance and approached the clinically important difference for fatigue. CONCLUSIONS/CLINICAL RELEVANCE: Reduction in wake disturbance was consistent with clinically meaningful difference standards for patient-reported outcomes, warranting further research in larger samples.

Serotonin transporter gene polymorphisms and depressive symptoms in patients with chronic obstructive pulmonary disease.

Background: We examined the relationship between polymorphisms in the promoter region of the serotonin transport (SERT) gene (5-HTTLPR, short 'S' and long 'L' alleles) and in intron 2 variable number tandem repeat (STin2VNTR, 9, 10, or 12-repeat alleles) with depression or anxiety in patients with COPD.Methods: 302 patients with moderate to severe COPD participated in SERT study. History and number of prior depressive episodes were measured using the Structured Clinical Interview for Depression; Hospital Anxiety Depression Scale (HAD) depression ≥8 or a Patient Health Questionnaire-9 (PHQ-9) >,10.Results: 240 (80%) male sample had a mean age of 68.0 years. Current depression was 22% (HAD) or 21% (PHQ-9), anxiety was 25% (HAD), and suicidal ideation (6%). 5-HTTLPR or STin2 VNTR genotypes were not associated with current depressive or anxiety symptoms. The mean number of prior depressive episodes was higher for patients with the 5-HTTLPR genotype S/S or S/L compared with L/L (4.4 ± 6.1; 5.3 ± 6.8; 4.0 ± 6.1, p < 0.001) and with STin2VNTR high-risk genotype (9/12 or 12/12), medium risk (9/10 or 10/12) compared to low risk (10/10) genotypes (5.1 ± 6.8; 4.9 ± 6.7; 2.7 ± 4.5, p < 0.001).Conclusions: SERT 5-HTTLPR and STin2-VNTR polymorphisms were not associated with current depressive and anxiety symptoms, but the high-risk STin2-VNTR genotypes and S/L were associated with the number of prior depressive episodes.

Stroke impact symptoms are associated with sleep-related impairment.

BACKGROUND: Sleep-related impairment is a common but under-appreciated complication after stroke and may impede stroke recovery. Yet little is known about factors associated with sleep-related impairment after stroke. OBJECTIVE: The purpose of this analysis was to examine the relationship between stroke impact symptoms and sleep-related impairment among stroke survivors. METHODS: We conducted a cross-sectional secondary analysis of a baseline (entry) data in a completed clinical trial with 100 community-dwelling stroke survivors recruited within 4 months after stroke. Sleep-related impairment and stroke impact domain symptoms after stroke were assessed with the Patient-Reported Outcomes Measurement Information System Sleep-Related Impairment scale and the Stroke Impact Scale, respectively. A multivariate regression was computed. RESULTS: Stroke impact domain-mood (B = -0.105, t = -3.263, p = .002) - and fatigue (B = 0.346, t = 3.997, p < .001) were associated with sleep-related impairment. CONCLUSIONS: Our findings suggest that ongoing stroke impact symptoms are closely related to sleep-related impairment. An intervention targeting both stroke impact symptoms and sleep-related impairment may be useful in improving neurologic recovery and quality of life in stroke survivors.

The serotonin transporter polymorphism rs25531 is associated with irritable bowel syndrome.

Irritable bowel syndrome is a frequent gastrointestinal disorder of unknown etiology. The serotonin transporter regulates the intensity and duration of serotonin signaling in the gut and is, therefore, an attractive candidate gene for irritable bowel syndrome. Previous studies investigating the 5-HTTLPR and Stin2 VNTR polymorphisms of the serotonin transporter have proved inconclusive. In this exploratory study we therefore expanded the search for a possible association of the serotonin transporter with irritable bowel syndrome to include not only the 5-HTTLPR and Stin2 VNTR length polymorphisms, but also the functional single nucleotide polymorphism rs25531. We genotyped 186 patients with irritable bowel syndrome and 50 healthy control subjects raging in age from 18 to 70 years. Carriers of the rare G allele of rs25531 had approximately threefold increased odds of irritable bowel syndrome compared with healthy controls (OR 3.3, 95% CI 1.1-9.6). Our findings suggest that further investigation of the possible role of the serotonin transporter in the etiology of IBS is warranted.

Living well with stroke: design and methods for a randomized controlled trial of a psychosocial behavioral intervention for poststroke depression.

BACKGROUND: Depression is a sufficiently common sequela of a completed stroke to warrant intervention to improve mood, social, and functional outcome. Pharmacologic trials suggest short-term mood improvement from antidepressant treatment but no studies to date have determined whether these short-term gains can be enhanced and extended by a brief psychosocial/behavioral intervention delivered by advanced practice nurses. In addition, drug trials have not reported on functional outcomes such as limitations in ability, limitations in participation, and overall quality of survival. This randomized controlled trial was designed to evaluate the short- and long-term efficacy of a new brief psychosocial/behavioral intervention adjunctive to antidepressant treatment in reducing poststroke depression and improving functional outcomes. METHODS: A total of 101 survivors of ischemic stroke with poststroke depression were randomly assigned to receive a brief psychosocial/behavioral intervention plus antidepressant or usual care, including antidepressants. RESULTS: The primary outcome was reduction in depressive symptom severity (Hamilton Depression Rating Scale) at 12 months after stroke. Secondary outcomes were reductions in limitations in activity (Barthel Index), reduction in limitation in participation, and overall stroke impact (Stroke Impact Scale) at 6, 12, and 24 months poststroke. Factors influencing best response to psychosocial intervention were also explored. CONCLUSION: This article provides detail on the design and treatment methods of this randomized trial in progress. Findings from this study provide important information regarding the long-term efficacy of such a behavioral intervention in reducing poststroke depression and subsequent impaired aspects of psychosocial and physical recovery.

Relationship of SERT polymorphisms to depressive and anxiety symptoms in irritable bowel syndrome.

This study investigates the association of psychological symptoms with the distribution of two serotonin transporter gene (SERT) polymorphisms, located in the promoter region (5-HTTLPR) and in intron 2 (STin2 VNTR), in patients with irritable bowel syndrome (IBS). Participants, 21 men and 117 women, were assessed for mental health history and current psychological distress. A blood sample was used for genotyping. Participants who were homozygous for the short allele of 5-HTTLPR or carried a STin2.9 VNTR allele were significantly more likely to have a history of depression. Participants did not differ by genotype in their history of anxiety or suicidal ideation nor in their current levels of depression, anxiety, or general psychological distress. The results support a biopsychosocial model of IBS in which SERT genotype modifies the risk for depressive episodes. Long term, practitioners may individualize treatment of patients with IBS using genotype as one of the factors.

Randomized trial of telephone versus in-person delivery of a brief psychosocial intervention in post-stroke depression.

BACKGROUND: A psychosocial behavioral intervention delivered in-person by advanced practice nurses has been shown effective in substantially reducing post-stroke depression (PSD). This follow-up trial compared the effectiveness of a shortened intervention delivered by either telephone or in-person to usual care. To our knowledge, this is the first of current behavioral therapy trials to expand the protocol in a new clinical sample. 100 people with Geriatric Depression Scores ≥ 11 were randomized within 4 months of stroke to usual care (N = 28), telephone intervention (N = 37), or in-person intervention (N = 35). Primary outcome was response [percent reduction in the Hamilton Depression Rating Scale (HDRS)] and remission (HDRS score < 10) at 8 weeks and 12 months post treatment. RESULTS: Intervention groups were combined for the primary analysis (pre-planned). The mean response in HDRS scores was 39% reduction for the combined intervention group (40% in-person; 38% telephone groups) versus 33% for the usual care group at 8 weeks (p = 0.3). Remission occurred in 37% in the combined intervention groups at 8 weeks versus 27% in the control group (p = 0.3) and 44% intervention versus 36% control at 12 months (p = 0.5). While favouring the intervention, these differences were not statistically significant. CONCLUSIONS: A brief psychosocial intervention for PSD delivered by telephone or in-person did not reduce depression significantly more than usual care. However, the comparable effectiveness of telephone and in-person follow-up for treatment of depression found is important given greater accessibility by telephone and mandated post-hospital follow-up for comprehensive stroke centers. Clinical Trial Registration URL: https://register.clinicaltrials.gov , unique identifier: NCT01133106, Registered 5/26/2010.

Rare Variants of the Serotonin Transporter Are Associated With Psychiatric Comorbidity in Irritable Bowel Syndrome.

Alterations in serotonin signaling are suspected in the pathophysiology of irritable bowel syndrome (IBS). By modulating the extracellular reuptake of serotonin, the serotonin transporter (SERT) acts as a key regulator of the bioavailability of serotonin. This study is the first to investigate the impact of rare SERT variants (i.e., those with a minor allele frequency of < 1%) on the risk for IBS, gastrointestinal (GI) symptom level, response to cognitive-behavioral treatment, and psychiatric comorbidity. We sequenced a 0.19 megabase chromosomal stretch containing the SERT gene and surrounding regions in a community sample of 304 IBS patients and 83 controls. We found no significant associations between rare variants in and around the SERT gene and IBS risk, GI symptom profile, or response to treatment. We found preliminary evidence, however, that IBS subjects with a history of either depression or anxiety were significantly more likely to carry multiple rare likely functional variant alleles than IBS patients without psychiatric comorbidity.

Overexpression of 5-HT1B receptor in dorsal raphe nucleus using Herpes Simplex Virus gene transfer increases anxiety behavior after inescapable stress.

5-HT(1B) autoreceptors have been implicated in animal models of stress and are regulated selectively by serotonin-selective reuptake inhibitors such as fluoxetine. These terminal autoreceptors regulate serotonin release from dorsal raphe nucleus (DRN) projections throughout rat forebrain. However, it has not been previously possible to manipulate 5-HT(1B) autoreceptor activity selectively without also changing 5-HT(1B) activity in other neurons mediating different behavioral responses. Therefore, we have developed a viral-mediated gene transfer strategy to express hemagglutinin-tagged 5-HT(1B) and manipulate these autoreceptors in DRN. Green fluorescent protein (GFP) was coexpressed from a separate transcriptional unit on the same amplicon to assist in monitoring infection and expression. We confirmed the expression and biological activity of both transgenic proteins in vitro. When injected directly into DRN using stereotaxic procedure, HA-5-HT(1B) receptors were expressed in serotonergic neurons and translocated to the forebrain. The effect of DRN expression of HA-5-HT(1B) on stress-induced behaviors was compared with control rats that received GFP-only amplicons. There was no change in immobility in the forced swim test. However, HA-5-HT(1B) expression significantly reduced entrances into the central region of an open-field arena after water-restraint stress without altering overall locomotor activity, but not in the absence of stress exposure. HA-5-HT(1B) expression also reduced entries into the open arms of the elevated plus maze after water restraint. Because these tests are sensitive to increases in anxiety-like behavior, our results suggest that overactivity of 5-HT(1B) autoreceptors in DRN neurons may be an important mediator of pathological responses to stressful events.

Examining gene-environment interactions in comorbid depressive and disruptive behavior disorders using a Bayesian approach.

OBJECTIVE: The objective of this study was to apply a Bayesian statistical analytic approach that minimizes multiple testing problems to explore the combined effects of chronic low familial support and variants in 12 candidate genes on risk for a common and debilitating childhood mental health condition. METHOD: Bayesian mixture modeling was used to examine gene by environment interactions among genetic variants and environmental factors (family support) associated in previous studies with the occurrence of comorbid depression and disruptive behavior disorders youth, using a sample of 255 children. RESULTS: One main effect, variants in the oxytocin receptor (OXTR, rs53576) was associated with increased risk for comorbid disorders. Two significant gene × environment and one signification gene × gene interactions emerged. Variants in the nicotinic acetylcholine receptor α5 subunit (CHRNA5, rs16969968) and in the glucocorticoid receptor chaperone protein FK506 binding protein 5 (FKBP5, rs4713902) interacted with chronic low family support in association with child mental health status. One gene × gene interaction, 5-HTTLPR variant of the serotonin transporter (SERT/SLC6A4) in combination with µ opioid receptor (OPRM1, rs1799971) was associated with comorbid depression and conduct problems. CONCLUSIONS: Results indicate that Bayesian modeling is a feasible strategy for conducting behavioral genetics research. This approach, combined with an optimized genetic selection strategy (Vrieze et al., 2012), revealed genetic variants involved in stress regulation (FKBP5, SERT × OPMR), social bonding (OXTR), and nicotine responsivity (CHRNA5) in predicting comorbid status.

Prevalence and correlates of suicide ideation in patients with COPD: a mixed methods study.

PURPOSE: The purpose of this study was to examine the prevalence and correlates of suicidal ideation (SI) in patients with stable moderate to very severe chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We conducted an exploratory mixed methods analysis of data from participants in a longitudinal observational study of depression in COPD. We measured depression with the Patient Health Questionnaire-9 (PHQ-9), which includes an item on SI. We compared participants with and without SI in relation to sociodemographics, symptoms, anxiety, and healthcare resource use with independent t-tests and chi-square tests. Content analysis was performed on qualitative data gathered during a structured SI safety assessment. RESULTS: Of 202 participants, 121 (60%) had depressive symptoms (PHQ ≥6); 51 (25%) had a PHQ-9 ≥10, indicating a high likelihood of current major depression; and 22 (11%) reported SI. Compared to the 99 depressed participants without SI, those with SI were more likely to be female (59% vs 27%, P=0.004); had worse dyspnea (P=0.009), depression (P<0.001), and anxiety (P=0.003); and were also more likely to have received treatment for depression and/or anxiety (82% vs 40%, P<0.001) and more hospitalizations for COPD exacerbations (P=0.03) but had similar levels of airflow obstruction and functioning than participants without SI. Themes from the qualitative analysis among those with SI included current or prior adverse life situations, untreated or partially treated complex depression, loss of a key relationship, experience of illness and disability, and poor communication with providers. CONCLUSION: Our findings suggest that current SI is common in COPD, may occur disproportionately in women, can persist despite mental health treatment, and has complex relationships with both health and life events. Adequate management of SI in COPD may therefore require tailored, comprehensive treatment approaches that integrate medical and mental health objectives.

Congenitally learned helpless rats show abnormalities in intracellular signaling.

BACKGROUND: Affective disorders and the drugs used to treat them lead to changes in intracellular signaling. We used a genetic animal model to investigate to what extent changes in intracellular signal transduction confer a vulnerability to mood or anxiety disorders. METHODS: Levels of gene expression in a selectively bred strain of rats with a high vulnerability to develop congenitally learned helplessness (cLH), a strain highly resistant to the same behavior (cNLH) and outbred Sprague-Dawley (SD) control animals were compared using quantitative reverse transcription polymerase chain reaction. RESULTS: Congenitally learned helpless animals had a 24%-30% reduced expression of the cyclic adenosine monophosphate response element binding protein messenger ribonucleic acid (mRNA) in the hippocampus and a 40%-41% increased level of the antiapoptotic protein bcl-2 mRNA in the prefrontal cortex compared to cNLH and SD rats. Other significant changes included changes in the expression levels of the alpha catalytic subunit of protein kinase A, glycogen synthase kinase 3beta, and protein kinase C epsilon. CONCLUSIONS: Congenitally learned helpless animals show evidence of altered signal transduction and regulation of apoptosis compared to cNLH and SD control animals.

TPH gene polymorphisms are associated with disease perception and quality of life in women with irritable bowel syndrome.

The aims of this exploratory study were to examine whether tryptophan hydroxylase (TPH) gene polymorphisms are associated with psychosocial factors in women with irritable bowel syndrome (IBS). TPH is the rate-limiting enzyme in the biosynthesis of serotonin and has two isoforms, TPH1 and TPH2. Four single nucleotide polymorphisms (SNPs) in the TPH1 gene and one SNP in the TPH2 gene were selected based on previous studies investigating associations between these SNPs and psychiatric or behavioral disorders. One hundred ninety-nine Caucasian women with IBS were included. Results of univariate analysis showed no association between TPH1and TPH2 gene SNPs and current level of psychological distress or psychiatric illness. However, TPH1 gene SNPs were associated with IBS-related cognitions (rs4537731 and rs21105) and quality of life (rs684302 and rs1800532), in particular the mental health and energy subscales. These associations were independent of the subjects' levels of gastrointestinal symptoms. These results suggest that patients' perception of their illness, and of the impact it has on their lives, may be subject to genetic influences, in this case sequence variants in TPH1. However, caution should be used in interpreting these results given the large number of hypothesis tests performed in this exploratory hypothesis-generating study, and the results should be considered tentative until confirmed in an independent sample.

A pilot investigation of the association of genetic polymorphisms regulating corticotrophin-releasing hormone with posttraumatic stress and depressive symptoms in medical-surgical intensive care unit survivors.

PURPOSE: To determine if single nucleotide polymorphisms of the corticotrophin-releasing hormone binding protein (CRHBP, rs10055255) and CRH receptor type 1 (CRHR1, rs1876831) were associated with posttraumatic stress disorder (PTSD) and depressive symptoms following medical-surgical intensive care unit (ICU) hospitalization. MATERIALS AND METHODS: We extracted DNA for genotyping from saliva samples of 93 ICU patients enrolled in a prospective cohort investigation. Follow-up interviews conducted 3 and 12-months post-ICU included assessment of PTSD symptoms with the PTSD Checklist-Civilian Version and depressive symptoms with the Patient Health Questionnaire-9. RESULTS: Homozygosity for the CRHBP rs10055255 T allele was associated with significantly fewer post-ICU PTSD (ß = -10.8, 95% confidence interval [95% CI], -17.7 to -3.9; P = .002) and depressive symptoms (ß = -3.7, 95% CI, -6.7 to -0.7; P = .02). Carrying a CRHR1 rs1876831 C allele was associated with significantly more post-ICU depressive symptoms compared to T/T homozygotes (C/T heterozygtes: ß = 6.9, 95% CI, 1.2-12.6; P = .02; C/C homozygotes: ß = 5.8; 95% CI: 0.2-11.3; P = .04). These associations remained significant after adjustment for age, race, illness severity, and in-ICU steroid exposure. CONCLUSIONS: Despite a small sample size, our findings suggest a potential role for genetic variants of CRHBP and CRHR1 in the development of post-ICU psychiatric morbidity.