Billy D. Nix

Improvement in Sexual Functioning in Patients With Type 2 Diabetes and Depression Treated With Bupropion

OBJECTIVE Major depressive disorder (MDD) and type 2 diabetes have independent adverse effects on sexual functioning (SF). Bupropion (BU) reportedly has few sexual side effects, but its use in diabetes has not been studied. RESEARCH DESIGN AND METHODS This article reports a planned secondary analysis of SF in 90 patients with type 2 diabetes treated with BU for MDD. RESULTS At baseline, 71.1% of patients had insufficient SF. Mean Sexual Energy Scale (SES) scores improved during treatment (P < 0.0001), as did the percentage with sufficient SF (30.6 vs. 68.1%, P = 0.001). Patients with persistent hyperglycemia had higher rates of sexual dysfunction; however, SES improvement was evident in some with persistent depression or hyperglycemia (18.2% and 25.9%, respectively). CONCLUSIONS Insufficient SF is prevalent and may be suspected in patients with MDD and type 2 diabetes. BU treatment of MDD had few sexual side effects and was associated with significant improvements in SF.

Genetic variation in the beta-2 adrenergic receptor (ADRB2) predicts functional gastrointestinal diagnoses and poorer health-related quality of life

The beta‐2 adrenergic receptor (ADRB2) is an important target for epinephrine, a neurotransmitter in pain signalling. ADRB2 haplotypes affect receptor expression and ligand response, and have been linked to painful non‐GI disorders.

Beliefs about GI medications and adherence to pharmacotherapy in functional GI disorder outpatients.

Objectives:Pharmacotherapy is a mainstay in functional gastrointestinal (GI) disorder (FGID) management, but little is known about patient attitudes toward medication regimens. Understanding patient concerns and adherence to pharmacotherapy is particularly important for off-label medication use (e.g., antidepressants) in FGID.Methods:Consecutive tertiary GI outpatients completed the Beliefs About Medications questionnaire (BMQ). Subjects were categorized as FGID and structural GI disease (SGID) using clinician diagnoses and Rome criteria; GI-specific medications and doses were recorded, and adherence to medication regimens was determined by patient self-report. BMQ domains (overuse, harm, necessity, and concern) were compared between FGID and SGID, with an interest in how these beliefs affected medication adherence. Psychiatric measures (depression, anxiety, and somatization) were assessed to gauge their influence on medication beliefs.Results:A total of 536 subjects (mean age 54.7±0.7 years, range 22–100 years; n=406, 75.7% female) were enrolled over a 5.5-year interval: 341 (63.6%) with FGID (IBS, 64.8%; functional dyspepsia, 51.0%, ≥2 FGIDs, 38.7%) and 142 (26.5%) with SGID (IBD, 28.9%; GERD, 23.2%). PPIs (n=231, 47.8%), tricyclic antidepressants (TCAs) (n=167, 34.6%), and anxiolytics (n=122, 25.3%) were common medications prescribed. FGID and SGID were similar across all BMQ domains (P>0.05 for overuse, harm, necessity, and concern). SGID subjects had higher necessity-concern framework (NCF) scores compared with FGID subjects (P=0.043). FGID medication adherence correlated negatively with concerns about medication harm (r=−0.24, P<0.001) and overuse (r=−0.15, P=0.001), whereas higher NCF differences predicted medication compliance (P=0.006). Medication concern and overuse scores correlated with psychiatric comorbidity among FGID subjects (P<0.03 for each). FGID patients prescribed TCAs (n=142, 41.6%) expressed a greater medication necessity (17.4±0.4 vs. 16.2±0.4, P=0.024) and found their GI regimen to be more helpful (P=0.054). FGID subjects not on TCAs expressed a greater apprehension about medication overuse (10.7±0.3 vs. 9.7±0.2, P=0.002) on the BMQ.Conclusions:FGID subjects report medication necessity and concern scores comparable to patients with SGID but have negative perceptions about medications, particularly in the presence of psychiatric comorbidity; these factors may affect treatment adherence and willingness to initiate neuromodulator regimens.

Genetic risk factors for perception of symptoms in GERD: an observational cohort study

Genetic polymorphisms in G‐protein beta‐3 subunit (GNβ3) and beta‐2 adrenergic receptor (ADRB2) are associated with pain and gut hypersensitivity, which can overlap with gastroesophageal reflux disease (GERD).

Opioid medication use in patients with gastrointestinal diagnoses vs unexplained gastrointestinal symptoms in the US Veterans Health Administration

While opioid prescriptions have increased alarmingly in the United States (US), their use for unexplained chronic gastrointestinal (GI) pain (eg, irritable bowel syndrome) carries an especially high risk for adverse effects and questionable benefit.

Mo1278 Review of Systems and Medication Allergies Predict Presence and Severity of Functional GI Disorders (FGIDs)

Background: IBS is a common functional GI syndrome with a prominent pain component. History of physical, sexual, and/or emotional abuse is more prevalent among IBS sufferers. Previously we reported that abuse is linked to more severe and frequent IBS symptoms and poorer health related quality of life (HRQOL). If abuse experiences heighten brain neurocircuitry sensitivity to pain experiences as has been suggested (Ringel Y et al Gastroenterol 2008), this study then sought to examine the effects of an abuse history on rates of functional GI disorder (FGID) diagnoses, non-GI diagnoses, and recent pain symptoms among an IBS population; further, we aimed to determine whether experiences of multiple forms of abuse resulted in greater likelihood of developing functional GI and non-GI complaints. Methods: Consecutive GI outpatients were invited to complete ROME III Research Diagnostic Questionnaire to establish FGID criteria. Self-report questionnaires on abuse history (Life-Stress Questionnaire) were obtained, with a focus on physical, sexual, and emotional abuse. IBS patients with histories of any form of these abuse experiences were defined as IBS+/Abuse+. Recent non-GI somatic symptoms (PHQ-12), and historical somatic pain diagnoses (e.g., fibromyalgia, headache, chronic back pain) were recorded. 272 ROMEdefined IBS subjects (50.1±0.9 yrs, 81% female) were identified, and reported greater rates of abuse compared to a non-IBS comparator group (n=246): physical (18.1% vs 6.6%), sexual (15.5% vs 7.4%), and emotional (31.7% vs 16.9%) (p 1 form of abuse. Compared to IBS subjects without abuse histories (IBS+/Abuse-), IBS+/Abuse+ subjects had greater total numbers of ROME diagnoses (2.5±0.3 vs 2.1±0.3, p=0.10), non-GI pain diagnoses (1.9±0.2 vs. 0.9±0.08, p<0.001), and more recent somatic symptoms (9.6±0.5 vs. 7.7±0.4, p=0.001). All forms of abuse experiences imposed similar risk of functional syndromes. An additive effect of multiple forms of abuse was observed, such that greater numbers non-GI pain disorders (F=13.5, p<0.001) and somatic symptom complaints (F=5.8, p=0.001) were noted with the experience of multiple forms of abuse. This additive effect was not relevant to the number of ROME diagnoses recorded, however (F=0.69, p=0.55). Conclusions: Abuse experiences common in IBS patients are associated with reports of greater non-GI symptoms, historical somatic diagnoses, and to a lesser extent additional FGID diagnoses in IBS patients; these relationships are particularly robust when multiple forms of abuse have been experienced. These observations provide indirect evidence of an enhanced susceptibility to both GI and somatic functional disorders following abuse.

Mo1276 Abuse Histories Predict Greater Functional GI and Pain Comorbidities in Irritable Bowel Syndrome (IBS) Patients

Background: IBS is a common functional GI syndrome with a prominent pain component. History of physical, sexual, and/or emotional abuse is more prevalent among IBS sufferers. Previously we reported that abuse is linked to more severe and frequent IBS symptoms and poorer health related quality of life (HRQOL). If abuse experiences heighten brain neurocircuitry sensitivity to pain experiences as has been suggested (Ringel Y et al Gastroenterol 2008), this study then sought to examine the effects of an abuse history on rates of functional GI disorder (FGID) diagnoses, non-GI diagnoses, and recent pain symptoms among an IBS population; further, we aimed to determine whether experiences of multiple forms of abuse resulted in greater likelihood of developing functional GI and non-GI complaints. Methods: Consecutive GI outpatients were invited to complete ROME III Research Diagnostic Questionnaire to establish FGID criteria. Self-report questionnaires on abuse history (Life-Stress Questionnaire) were obtained, with a focus on physical, sexual, and emotional abuse. IBS patients with histories of any form of these abuse experiences were defined as IBS+/Abuse+. Recent non-GI somatic symptoms (PHQ-12), and historical somatic pain diagnoses (e.g., fibromyalgia, headache, chronic back pain) were recorded. 272 ROMEdefined IBS subjects (50.1±0.9 yrs, 81% female) were identified, and reported greater rates of abuse compared to a non-IBS comparator group (n=246): physical (18.1% vs 6.6%), sexual (15.5% vs 7.4%), and emotional (31.7% vs 16.9%) (p 1 form of abuse. Compared to IBS subjects without abuse histories (IBS+/Abuse-), IBS+/Abuse+ subjects had greater total numbers of ROME diagnoses (2.5±0.3 vs 2.1±0.3, p=0.10), non-GI pain diagnoses (1.9±0.2 vs. 0.9±0.08, p<0.001), and more recent somatic symptoms (9.6±0.5 vs. 7.7±0.4, p=0.001). All forms of abuse experiences imposed similar risk of functional syndromes. An additive effect of multiple forms of abuse was observed, such that greater numbers non-GI pain disorders (F=13.5, p<0.001) and somatic symptom complaints (F=5.8, p=0.001) were noted with the experience of multiple forms of abuse. This additive effect was not relevant to the number of ROME diagnoses recorded, however (F=0.69, p=0.55). Conclusions: Abuse experiences common in IBS patients are associated with reports of greater non-GI symptoms, historical somatic diagnoses, and to a lesser extent additional FGID diagnoses in IBS patients; these relationships are particularly robust when multiple forms of abuse have been experienced. These observations provide indirect evidence of an enhanced susceptibility to both GI and somatic functional disorders following abuse.

NOD2 and ATG16L1-A197T Polymorphisms Do Not Confer Risk for Irritable Bowel Syndrome

Genomewide association studies demonstrate that genetic polymorphisms in genes associated with alterations in innate immune function (e.g., NOD2 and ATG16L1) confer risk for inflammatory bowel disease (IBD), specifically Crohns disease (CD). Patients with irritable bowel syndrome (IBS) can also have alterations in their intestinal flora and increased innate immune system activation, potentially leading to low grade inflammation and consequent gastrointestinal symptoms (Ohman et al., Nat Rev Gastroenterol Hepatol 2010). We tested the hypothesis that polymorphisms in NOD2 and ATG16L1 may contribute to the putative derangement in innate immune response underlying IBS pathogenesis. Objectives:We sought to determine if polymorphisms inNOD2 (rs2066847, rs2066844, rs2066845) and ATG16L1A197T (rs2241880), known to confer risk for IBD are also associated with an increased risk of IBS compared to healthy individuals. Methods: Our institutional GI patient database and tissue repository was interrogated to identify subjects with IBS (n=201, 46.4 ±14.5 yr, 66.2%F), CD (n=829; 44.8 ±14.9 yr, 56.9%F), ulcerative colitis (UC, n=325, 45.6 ±15.1 yr, 48%F), or healthy controls (HC) without any gastrointestinal pathology (n=171, 56.6 ±16.0 yr, 52.6%F). Diagnosis of CD and UC required conclusive histopathologic evidence from surgical resection specimens or mucosal biopsy specimens at endoscopy in subjects with compatible clinical and laboratory profiles. Sequenom MassARRAY was used for single nucleotide polymorphism (SNP) genotyping. Inter-group differences in genotypes were assessed by Chi-square analysis. Results: Allele frequencies were in Hardy-Weinberg equilibrium for each of the examined SNPs. As expected, the presence of at least one NOD2 risk allele was significantly more common in CD subjects (267/829, 32.2%) compared to UC (44/325, 13.5%), IBS (27/201, 13.4%), or HC (30/171, 17.5%); p 0.05). There was a significant (p=0.042) difference in G allele frequency of ATG 16L1-A197T when CD subjects (80.3%) were compared with HC (70.1%), or IBS (71.4%). The G allele frequency in ATG 16L1-A197T in UC subjects (75.7%) was similar to HC and IBS (p>0.05). Conclusions: The evaluated polymorphisms in NOD2 and ATGL1 do not conspicuously function as risk alleles for IBS. These findings provide indirect evidence that alterations in the innate immune system described in IBS have a unique yet undiscovered mechanism for pathogenesis and symptom generation; this mechanism may be distinct from that commonly seen and acknowledged in Crohns disease. Future investigations with genome wide association studies are needed to confirm this hypothesis and further explore the potential role of alleles linked to innate immunity in IBS pathogenesis.

The Relationship of Overlapping Affective and Somatization Symptoms With Homeostatic Afferent Processing Network Activations in Irritable Bowel Syndrome (IBS)

Background: Brain activation differences in response to painful visceral stimuli previously have been reported in IBS compared to healthy controls, and often are observed within the homeostatic afferent processing network (HAPN). While HAPN regions are involved in emotional and cognitive responses to pain (Mayer E., et al. Gastroenterol 2006), many of these same brain regions also are also implicated in affective disorder pathogenesis. IBS brain activation patterns with noxious stimulation are inconsistent across studies, possibly in part due to the psychiatric heterogeneity in IBS. We hypothesized that affective and somatization symptoms may influence observed abnormal HAPN pain responses in IBS subjects. Methods: 16 right-handed female IBS subjects (45.8 ±10.3 yr old) and 16 healthy controls (40.7 ±10.7 yr old) completed the PHQ-15 somatization index and recent affective symptom measures (Beck Depression (BDI) and Anxiety (BDI) Inventories). All subjects underwent functional MRI (fMRI) imaging in a Seimens Trio 3.0T scanner, during randomized visceral stimulation (rectal balloon distension) at low(LP, 25-mmHg) and higher-pressure (HP, 50-mmHg) levels. Regions where IBS response to rectal distention was significantly different from controls were identified in ANOVA analyses. Linear regression models subsequently were developed to assess affective and somatization symptoms as predictors of HAPN activations, and mediation analysis explored affective symptoms as potential intervening variables in the relationship between somatization and brain activations. Results: BDI, BAI, and PHQ-15 scores all were higher in IBS vs. control subjects (p 0.70, p<0.001). Significant IBS-control activation differences were identified in several HAPN regions, including the L amygdala, pregenual/rostral ACC (BA 32), and BA 10, as well as B anterior/posterior insula, middle frontal gyrus (BA 8/9, 47) and thalamus (p <0.01 for each). In separate regression models, BAI scores predicted HAPN activation in the L amygdala, pregenual ACC, mid/posterior insula, BA 8/9, BA10, and R BA 47, posterior insula, and BA 9. PHQ-15 scores predicted HAPN activations in these same regions except L BA 10 (BDI scores predicted activation only in the L amygdala and BA32.) Mediation analyses failed to identify either anxiety or depression as intermediates in the observed somatization-HAPN activation relationship. Discussion: IBS-control HAPN activation differences were predicted by anxiety and somatization, and to a limited extent by depression symptoms. Despite their high correlation, anxiety and somatization appear to independently influence HAPN activations. Routine measurement of recent somatization and affective symptoms, particularly anxiety, may be important in the interpretation of future IBS neuroimaging studies.