Mrazek, David A.

Abstract Background and Aims Depression and anxiety are often comorbid with alcoholism and contribute to craving and relapse. We aimed to estimate the prevalence of life‐time diagnoses of major depressive disorder (MDD), substance‐induced depression (SID), anxiety disorder (AnxD) and substance‐induced anxiety (SIA), the effects of these comorbidities on the propensity to drink in negative emotional states (negative craving), and test whether these effects differ by sex. Design Secondary analyses of baseline data collected in a single‐arm study of pharmacogenetic predictors of acamprosate response. Setting Academic medical center and affiliated community‐based treatment programs in the American upper mid‐west. Participants A total of 287 males and 156 females aged 18–80 years, meeting DSM‐IV criteria for alcohol dependence. Measurements The primary outcome measure was ‘propensity to drink in negative emotional situations’ (determined by the Inventory of Drug Taking Situations) and the key predictors/covariates were sex and psychiatric comorbidities, including MDD, SID, AnxD and SIA (determined by Psychiatric Research Interview of Substance and Mood Disorders). Findings The prevalence of the MDD, SID and AnxD was higher in females compared with males (33.1 versus 18.4%, 44.8 versus 26.4% and 42.2 versus 27.4%, respectively; P < 0.01, each), while SIA was rare (3.3%) and did not differ by sex. Increased propensity to drink in negative emotional situations was associated with comorbid MDD (β = 6.6, P = 0.013) and AnxD (β = 4.8, P = 0.042) as well as a SID × sex interaction effect ( P = 0.003), indicating that the association of SID with propensity to drink in negative emotional situations differs by sex and is stronger in males (β = 7.9, P = 0.009) compared with females (β = −6.6, P = 0.091). Conclusions There appears to be a higher prevalence of comorbid depression and anxiety disorders as well as propensity to drink in negative emotional situations in female compared with male alcoholics. Substance‐induced depression appears to have a sex‐specific effect on the increased risk for drinking in negative emotional situations in males.

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.

Background and ObjectivesThe aim of this study was to investigate potential gender differences in situations associated with heavy alcohol drinking.MethodsData 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.ResultsWomen 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 SignificanceOur 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. (Am J Addict 2013;22:437–442)

AbstractSynthetic 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.

AbstractTo 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.

OBJECTIVE. We investigated the prevalence and types of psychiatric disorders diagnosed by early adulthood among patients who had common forms of strabismus as children. METHODS. The medical records of children (&lt;19 years) who were diagnosed as having esotropia (N = 266) or exotropia (N = 141) while residents of Olmsted County, Minnesota, between January 1, 1985, and December 31, 1994, were reviewed retrospectively for psychiatric disease diagnoses. Each case subject was compared with a randomly selected, individually birth- and gender-matched, control subject from the same population. RESULTS. A mental health disorder was diagnosed for 168 (41.3%) of the 407 patients with a history of childhood strabismus, who were monitored to a mean age of 17.4 years, compared with 125 control subjects (30.7%). Children with exotropia were 3.1 times more likely to develop a psychiatric disorder than were control subjects when monitored to a mean age of 20.3 years. Children with esotropia were no more likely to develop mental illness than were control subjects when monitored for similar periods. Patients with intermittent exotropia also were significantly more likely to have greater numbers of mental health disorders, mental health emergency department visits, and mental health hospitalizations and to have suicidal or homicidal ideation. CONCLUSIONS. Children diagnosed as having strabismus in this population, especially those with exotropia, were at increased risk for developing mental illness by early adulthood. Patients with intermittent exotropia seemed to be particularly prone to developing significant psychiatric diseases by the third decade of life.