Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons.

Disrupted serotonergic neurotransmission has long been implicated in major depressive disorder (MDD), for which selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment. However, a significant percentage of patients remain SSRI-resistant and it is unclear whether and how alterations in serotonergic neurons contribute to SSRI resistance in these patients. Induced pluripotent stem cells (iPSCs) facilitate the study of patient-specific neural subtypes that are typically inaccessible in living patients, enabling the discovery of disease-related phenotypes. In our study of a well-characterized cohort of over 800 MDD patients, we generated iPSCs and serotonergic neurons from three extreme SSRI-remitters (R) and SSRI-nonremitters (NR). We studied serotonin (5-HT) biochemistry and observed no significant differences in 5-HT release and reuptake or in genes related to 5-HT biochemistry. NR patient-derived serotonergic neurons exhibited altered neurite growth and morphology downstream of lowered expression of key Protocadherin alpha genes as compared to healthy controls and Rs. Furthermore, knockdown of Protocadherin alpha genes directly regulated iPSC-derived neurite length and morphology. Our results suggest that intrinsic differences in serotonergic neuron morphology and the resulting circuitry may contribute to SSRI resistance in MDD patients.

Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons.

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.

The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression.

Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.

Validation of the 17-item Hamilton Depression Rating Scale definition of response for adults with major depressive disorder using equipercentile linking to Clinical Global Impression scale ratings: analysis of Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) data.

OBJECTIVE: The study aimed to define thresholds of clinically significant change in 17-item Hamilton Depression Rating Scale (HDRS-17) scores using the Clinical Global Impression-Improvement (CGI-I) Scale as a gold standard. METHODS: We conducted a secondary analysis of individual patient data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study, an 8-week, single-arm clinical trial of citalopram or escitalopram treatment of adults with major depression. We used equipercentile linking to identify levels of absolute and percent change in HDRS-17 scores that equated with scores on the CGI-I at 4 and 8 weeks. Additional analyses equated changes in the HDRS-7 and Bech-6 scale scores with CGI-I scores. RESULTS: A CGI-I score of 2 (much improved) corresponded to an absolute decrease (improvement) in HDRS-17 total score of 11 points and a percent decrease of 50-57%, from baseline values. Similar results were observed for percent change in HDRS-7 and Bech-6 scores. Larger absolute (but not percent) decreases in HDRS-17 scores equated with CGI-I scores of 2 in persons with higher baseline depression severity. CONCLUSIONS: Our results support the consensus definition of response based on HDRS-17 scores (>50% decrease from baseline). A similar definition of response may apply to the HDRS-7 and Bech-6. Copyright © 2016 John Wiley & Sons, Ltd.

The role of gabapentin in the management of alcohol withdrawal and dependence.

OBJECTIVE: To review the literature evaluating gabapentin for alcohol withdrawal and dependence. DATA SOURCES: A literature search of MEDLINE (1966 to end of March 2015) and PubMed was performed using the terms alcohol, gabapentin, withdrawal, and dependence. Additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: English-language prospective studies evaluating gabapentin for alcohol withdrawal and dependence were evaluated. DATA SYNTHESIS: A total of 10 publications utilizing gabapentin in alcohol withdrawal (n = 5) and alcohol dependence (n = 5) were included in this review. Limited data suggest that gabapentin can provide benefit in managing mild alcohol withdrawal syndrome. There were 5 reported or suspected seizures in the withdrawal studies, suggesting that additional safety data are necessary before gabapentin monotherapy can be routinely considered. Sleep and mood/anxiety-related outcomes were positively influenced by gabapentin, which may result in long-term benefits if continued beyond the withdrawal period for the treatment of alcohol dependence. Studies evaluating gabapentin for alcohol dependence demonstrated dose-dependent benefits for complete abstinence, rates of no heavy drinking, and cravings. Gabapentin used to treat alcohol dependence was well tolerated with no severe adverse reactions reported in the extant literature. CONCLUSION: Gabapentin may have a role in the treatment of mild alcohol withdrawal, but future studies should focus on adequate dosing strategies. Gabapentin should be considered for the treatment of alcohol dependence when barriers prevent the use of traditional agents. Additional studies should be conducted to further validate findings from the research conducted to date, but the current literature is promising for gabapentin in the treatment of alcohol dependence.

The association between sleep disturbances and alcohol relapse: A 12-month observational cohort study.

BACKGROUND: Sleep disturbances are extremely common in alcohol recovery. Systematic research into the relationship between alcohol relapse and sleep disturbances using validated scales and accounting for potential confounders is lacking. METHODS: Patients admitted to a 1-month residential addiction treatment program were administered the Pittsburg Sleep Quality Index (PSQI) at admission/discharge. In addition, the Alcohol Use Disorders Identification Test (AUDIT), Patient Health Questionnaire-9 (PHQ-9), and Pennsylvania Alcohol Craving Scale (PACS) were administered. Patients were contacted every 3 months over 1 year following discharge. Associations of clinical factors with time until relapse were examined using univariate Cox proportional hazard models. RESULTS: One-hundred and nineteen patients with alcohol use disorders met inclusion criteria (mean age 50.6 ± 13.2 years, 57% male), relapse data were available for 81 patients. Eighty percent of subjects had other psychiatric diagnoses, 66.3% had sleep disturbances at the time of admission, and 57.1% were using hypnotics; 49.1% of patients had sleep disturbances at discharge. Sleep disturbances at admission and discharge were not associated with alcohol relapse at 12 months (OR = 1.00, 95% CI = 0.89-1.13; p = 0.95 and OR = 0.97, 95% CI = 0.86-1.09; p = 0.61). The PSQI sub-scale scores were also not associated with relapse at 12 months. The use of alcohol to help fall asleep (OR = 3.26, 95% CI = 1.33-7.95; p = 0.008), hypnotic use at admission (OR = 4.03, 95% CI = 1.63-9.97; p = 0.002) and age (OR = 1.03, 95% CI = 1.00-1.06; p = 0.035) were associated with relapse over 12 months. CONCLUSION: In patients completing a residential treatment program, sleep disturbances as measured by the PSQI were not associated with alcohol relapse at 12 months. Alcohol use as a hypnotic and hypnotic use at admission were associated with subsequent relapse.

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.

Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.

AIMS: Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT. METHODS: Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects. RESULTS: Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. CONCLUSIONS: In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.

Association of GATA4 sequence variation with alcohol dependence.

To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol-dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.

The course of sleep disturbances in early alcohol recovery: an observational cohort study.

INTRODUCTION: Understanding the course and determinants of sleep disturbances in alcoholic patients may help identify patients at high risk of persistent sleep problems, relapse and guide treatment interventions. METHODS: We prospectively administered the Pittsburgh Sleep Quality Index (PSQI) to all patients (N = 196) admitted to a 1-month residential treatment program. Our analysis excluded patients with active drug abuse/dependence. Demographic data, psychiatric diagnoses, Patient Health Questionnaire-9 (PHQ-9), Alcohol Use Disorders Identification Test (AUDIT) and Inventory of Drug Taking Situations (IDTS) scores were obtained. Univariate and logistic regression analyses were performed using sex, age, hazardous alcohol use, PHQ-9 scores, hypnotic use, and use of alcohol as a hypnotic as correlates to admission PSQI scores and improvement in PSQI scores. RESULTS: A total of 119 alcoholic patients met inclusion criteria (mean age 50.6 ± 13.2 years). The rates of sleep disturbances at admission and discharge were 69.3% and 49.1%, respectively. Self report of using alcohol to fall asleep and use of hypnotics were associated with elevated PSQI scores. Total PSQI scores improved over 4 weeks (p < .001). Change in PSQI scores was not effected by gender, use of hypnotics, hazardous alcohol use, use of alcohol as a hypnotic or co-morbid psychiatric diagnosis. Older age predicted improvement in PSQI scores in patients with sleep disturbances (p = .004). CONCLUSION: While a large proportion of alcoholics had sleep disturbances upon admission and at discharge from a residential treatment program, only older age was associated with improvements in sleep disturbances during early alcohol recovery.

Therapeutic Content of Mobile Phone Applications for Substance Use Disorders: An Umbrella Review.

Mobile phone applications (MPAs) for substance use disorder (SUD) treatment are increasingly used by patients. Although pilot studies have shown promising results, multiple previous systematic reviews noted insufficient evidence for MPA use in SUD treatment-many of the previously published reviews evaluated different trials. Subsequently, we aimed to conduct an umbrella review of previously published reviews investigating the efficacy of MPAs for SUD treatment, excluding nicotine/tobacco because umbrella reviews have been done in this population and the nicotine/tobacco MPA approach often differs from SUD-focused MPAs. No previous reviews have included a statistical meta-analysis of clinical trials to quantify an estimated overall effect. Seven reviews met inclusion criteria, and 17 unique studies with available data were taken from those reviews for the meta-analysis. Overall, reviews reported a lack of evidence for recommending MPAs for SUD treatment. However, MPA-delivered recovery support services, cognitive behavioral therapy, and contingency management were identified across multiple reviews as having promising evidence for SUD treatment. Hedges g effect size for an MPA reduction in substance use-related outcomes relative to the control arm was insignificant (0.137; 95% CI, -0.056 to 0.330; P=.16). In subgroup analysis, contingency management (1.29; 95% CI, 1.088-1.482; τ 2=0; k=2) and cognitive behavioral therapy (0.02; 95% CI, 0.001-0.030; τ 2=0; k=2) were significant. Although contingency management's effect was large, both trials were small (samples of 40 and 30). This review includes an adapted framework for the American Psychiatric Association's MPA guidelines that clinicians can implement to review MPAs critically with patients.

Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting.

OBJECTIVE: The objective was to evaluate the potential benefit of an integrated, five-gene pharmacogenomic test and interpretive report (GeneSight) for the management of psychotropic medications used to treat major depression in an outpatient psychiatric practice. METHODS: The open-label study was divided into two groups. In the first (unguided) group (n = 113), pharmacogenomic information was not shared until all participants completed the study. In the second (guided) group (n = 114), the pharmacogenomic report was provided to physicians for clinical use. Three depression ratings, the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Quick Inventory of Depressive Symptomatology - Clinician Rated (QIDS-C16), and the Patient Health Questionnaire (PHQ-9), were collected at baseline, and at 2, 4, and 8 weeks. RESULTS: The guided group experienced greater percent improvement in depression scores from baseline on all three depression instruments (HAMD-17, P < 0.0001; QIDS-C16, P < 0.0001; PHQ-9, P < 0.0001) compared with the unguided group. Eight-week response rates were higher in the guided group than in the unguided group on all three measurements (HAMD-17, P = 0.03; QIDS-C16, P = 0.005; PHQ-9, P = 0.01). Eight-week QIDS-C16 remission rates were higher in the guided group (P = 0.03). Participants in the unguided group who at baseline were prescribed a medication that was most discordant with their genotype experienced the least improvement compared with other unguided participants (HAMD-17, P = 0.007). Participants in the guided group and on a baseline medication most discordant with their genotype showed the greatest improvement compared with the unguided cohort participants (HAMD-17, P = 0.01). CONCLUSION: These findings replicate previous studies and demonstrate significantly improved depression outcomes with use of GeneSight, an integrated, multigenetic pharmacogenomic testing platform.

Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states.

Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

A retrospective study of gender differences in depressive symptoms and risk of relapse in patients with alcohol dependence.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate potential gender differences in situations associated with heavy alcohol drinking. METHODS: Data from 395 alcohol dependent patients participating in the Mayo Clinic Intensive Addiction Program were evaluated. Each participant completed the inventory of drug taking situations (IDTS), Penn alcohol craving scale (PACS), patient health questionnaire (PHQ-9), and/or Beck depression inventory (BDI). Gender differences in IDTS scores representing three domains (negative, positive, and temptation) of situations associated with heavy alcohol use were examined. RESULTS: Women with alcohol dependence report a higher frequency of heavy drinking in unpleasant emotional (IDTS negative scores mean ± SD women vs. men: 52.3 ± 22.1 vs. 43.8 ± 21.8; p = .0006), and as a result of temptation (IDTS temptation scores mean ± SD women vs. men: 40.4 ± 23.0 vs. 35.3 ± 20.8; p = .035). Upon admission, women also scored significantly higher on depressive symptoms as measured by the BDI (23.4 ± 11.4 vs. 18.2 ± 9.8, p < .001). After controlling for depressive symptom severity as a covariate, the IDTS gender differences were no longer significant. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Our results suggest that unpleasant or temptation based emotional situations are a vulnerability risk factor for heavy drinking particularly in females. This risk appears to be at least partially driven by depressive symptom burden. Future research is needed to further investigate this finding.

Alcohol craving as a predictor of relapse.

BACKGROUND AND OBJECTIVES: Alcoholism treatment interventions, both psychosocial and pharmacologic, aim to reduce cravings to drink. Yet, the role of craving in treatment outcomes remains unclear. This study evaluated craving intensity measured with the Penn Alcohol Craving Scale (PACS) at admission and discharge from residential treatment as a predictive factor of relapse after treatment. METHODS: The study cohort included 314 alcohol-dependent subjects. Associations between relapse after discharge, PACS score, and clinical variables were investigated using time-to-event analyses. The primary analysis, based on the intent-to-treat principle, presumed relapse in those declining follow-up or not responding to contact attempts. Secondary analysis utilized data from 226 subjects successfully contacted after discharge with a median follow-up time of 365 days. RESULTS: The intent-to-treat analysis demonstrated that relapse was associated with higher level of craving at admission (p= .002) and discharge (p < .001). The analysis of data from patients successfully contacted after discharge led to similar results. A multivariable analysis indicated that relapse rates increased as PACS scores increased, and a higher discharge PACS score was significantly associated with relapse (p= .006) even after adjusting for covariates. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This study demonstrates that higher PACS scores at the time of admission and discharge are associated with relapse following residential addiction treatment. These data support the role of craving in relapse and the utility of craving measurement as a clinical guide in assessing relapse risk.

Trazodone and alcohol relapse: a retrospective study following residential treatment.

Trazodone is one of the most commonly prescribed hypnotic medications in patients with sleep disturbances in alcohol recovery. A recent study concluded that treating insomnia with trazodone in patients with alcohol dependence might impede improvements in alcohol consumption and lead to increased drinking when trazodone is stopped. We set out to investigate the relationship between trazodone use during alcoholism treatment and relapse rates in patients who were discharged from a residential alcohol treatment program. We retrospectively reviewed records of patients with a diagnosis of alcohol dependence in a residential addiction treatment center from 2005 to 2008 and analyzed the association of trazodone use at discharge and alcohol relapse at 6 months. We also assessed the association between trazodone use and relapse at 6 months adjusting for sex, drug dependence, nonsubstance use Axis I psychiatric diagnoses, patient self-report of difficulties with sleep, and anti-dipsotropic medication use at discharge and evaluated pair-wise interactions of trazodone use with the adjustment variables. Of 283 patients eligible for inclusion, 85 (30%) were taking trazodone at discharge. Older age, self-reported sleep problems, and having a nonsubstance use Axis I psychiatric diagnosis were associated with trazodone use. After discharge, 170 (60%) subjects responded to follow-up efforts. Neither intent to treat nor responder only analysis revealed any association between trazodone use and relapse. Our retrospective study of a complex patient population discharged from a residential treatment setting did not find an association between trazodone use at discharge and relapse rates at 6 months.

Utilization of residential alcoholism treatment in bipolar disorder.

Despite the high prevalence rate of comorbid alcohol dependence and bipolar disorder, little is known about how many bipolar patients are actively engaged in addiction treatment or the alcohol consumption characteristics of this group. This retrospective study reviewed the medical records from patients with alcohol dependence admitted to residential treatment at our institution (n = 588). The analyses focused on alcoholism severity measures and discharge clinical diagnoses. Patients with alcoholism + bipolar disorder compromised only 5% of the total study group. The number of drinking years was lower for patients with alcoholism + bipolar disorder (23.1 ± 17.7) than for those with alcoholism + depression (26.8 ± 13.9) or alcoholism alone (28.1 ± 13.2). A trend of higher mean lifetime maximum daily drinks was observed for patients with alcoholism + bipolar disorder; this was because of the significantly higher maximum drinks for women with bipolar disorder (21.0 ± 11.5) than for women in other diagnostic groups. Despite high rates of comorbidity in community-based studies, this retrospective study suggests that patients with bipolar disorder are not highly represented in residential alcoholism addiction treatment. Future studies are encouraged to better understand utilization rates of addiction treatment among patients with bipolar disorder and to identify clinical correlates that predispose bipolar women to high-dose drinking.

Telling the patient's story: using theatre training to improve case presentation skills.

A medical student's ability to present a case history is a critical skill that is difficult to teach. Case histories presented without theatrical engagement may fail to catch the attention of their intended recipients. More engaging presentations incorporate 'stage presence', eye contact, vocal inflection, interesting detail and succinct, well organised performances. They convey stories effectively without wasting time. To address the didactic challenge for instructing future doctors in how to 'act', the Mayo Medical School and The Mayo Clinic Center for Humanities in Medicine partnered with the Guthrie Theater to pilot the programme 'Telling the Patient's Story'. Guthrie teaching artists taught storytelling skills to medical students through improvisation, writing, movement and acting exercises. Mayo Clinic doctors participated and provided students with feedback on presentations and stories from their own experiences in patient care. The course's primary objective was to build students' confidence and expertise in storytelling. These skills were then applied to presenting cases and communicating with patients in a fresher, more engaging way. This paper outlines the instructional activities as aligned with course objectives. Progress was tracked by comparing pre-course and post-course surveys from the seven participating students. All agreed that the theatrical techniques were effective teaching methods. Moreover, this project can serve as an innovative model for how arts and humanities professionals can be incorporated for teaching and professional development initiatives at all levels of medical education.

Factors Having an Impact on Relapse and Survival in Transplant Recipients With Alcohol-Induced Liver Disease.

OBJECTIVE: To assess the impact of standardized pretransplant alcohol abstinence and treatment guidelines on liver transplant outcomes. METHODS: This study assessed the posttransplant relapse and survival associated with a pretransplant guideline mandating alcohol abstinence, addiction treatment, and Alcoholics Anonymous (AA) attendance. This retrospective cohort study included liver recipients with alcohol-induced liver disease transplanted between January 1, 2000, and December 31, 2012, at a Midwest transplant center. Cox regression models tested for associations between pretransplant treatment, demographic and clinical characteristics, and outcome measures. RESULTS: Of 236 liver recipients (188 [79.7%] male; 210 [89%] white; mean follow-up, 88.6±55.0 months), 212 (90.2%) completed pretransplant treatment and 135 (57.2%) attended AA weekly. At 5 years, 16.3% and 8.2% had relapsed to any alcohol use and to high-dose drinking, respectively. Smoking during the 6 months before transplant was associated with any relapse (P=.0002) and high-dose relapse (P<.0001), and smoking at transplant was associated with death (P=.001). High-dose relapse was associated with death (hazard ratio, 3.5; P<.0001). CONCLUSION: A transplant center with a guideline requiring abstinence, treatment, and AA participation experienced lower posttransplant relapse rates from those previously reported in comparable large US transplant programs. Smoking cessation may further improve posttransplant outcomes.