Recent findings support sex-specific effects of PDYN polymorphisms on association with opioid addiction (Clarke et al. 2012). We have demonstrated that PDYN haplotypes, which include rs2281285, are associated with alcohol dependence and propensity to drink in negative emotional situations (negative craving) (Karpyak et al 2012). The rs2281285 variant may contribute to regulation of alternative PDYN mRNA transcription specific to brain area or physiological condition.

To investigate sex-specific effects of the PDYN rs2281285 variant on risk for alcohol dependence.

To examine the association of the PDYN rs2281285 variant with alcohol dependence in male and female subjects.

rs2281285 was genotyped in the investigation cohort of 816 (554 males) alcohol dependent subjects (DSM-IV-TR) and 1248 (603 males) non-alcoholic controls and in the replication cohort of 467 (347 males) alcohol dependent subjects and 431 (224 males) non-alcoholic controls. Logistic regression models were used to test for sex-specific associations after controlling for age.

As previously reported, significant association of the PDYN rs2281285 variant with alcohol dependence was found in the investigation (p = 0.008, odds ratio = 1.299), but not the replication cohort (0.223, OR = 0.118). However, sex-specific analyses revealed stronger association in males (p = 0.002, OR = 1.493) but not females (p = 0.684, OR = 1.066) in the investigation cohort, and a trend for association in males (p = 0.086, OR = 1.352) but not females (p = 0.808, OR = 0.947) in the replication cohort.

Our findings support association of PDYN rs2281285 variant with alcohol dependence in male but not female subjects. Future studies should investigate functional mechanisms of this effect.

We recently identified association between GRIN2B rs2058878 variant and abstinence length in acamprosate-treated alcoholics (Karpyak et al. 2014). Here we present results of additional analyses exploring associations in the same sample (225 alcoholics treated with acamprosate for three months) at the gene and gene-set levels, for 12 genes involved in glycine signaling, 4 genes involved in glutamate reuptake, synthesis and degradation and 7 genes encoding NMDA receptor subunits.

After adjustment for relevant covariates, gene-level tests were performed using principal components (PC) analysis. Gene-set analyses were performed using the PC-Gamma approach with varying soft truncation threshold (STT) for the Gamma method for combining gene-level p-values.

Shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between last drink and initiation of acamprosate treatment. After adjustment for covariates, we observed nominally significant association of abstinence length with variation in the AMT (p=0.024), GRIN3A (p=0.016) and SHMT2 (p=0.039) genes, and marginally significant evidence for association with the GRIN2B (p=0.067) and GLRB (p=0.060) genes. At the gene-set level, association of abstinence length with variation in the glycine pathway was nominally significant (p=0.042 with STT=0.37). Marginal evidence of association with abstinence length was also observed for variation in the NMDA-receptor subunits (p<0.1 for STT<0.15).

Our findings suggest association of abstinence length in acamprosate-treated alcoholics with variation in the glycine signaling pathway and genes encoding NMDA receptor subunits. Investigation of the mechanisms underlying these associations and their usefulness for individualized treatment selection should follow.

Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.

The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.

There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.

These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

This study examined healthcare utilization in the past year by subjects who screened positive for bipolar versus unipolar depression.

A self-administered survey was completed in 2002 by a United States population-based sample. Respondents were categorized into one of three subgroups: bipolar depressed screen positive (BP DEP+, n=394); unipolar depressed screen positive (UP DEP+, n=794); and control subjects (n=1,612).

For depressive symptoms in the past year, BP DEP+ respondents were significantly more likely than UP DEP+ respondents to report a healthcare visit to a number of diverse care providers. In analyses controlled for demographics and depression severity, the differences in psychiatric hospitalization, psychologist/counselor outpatient visit, substance abuse/social services visit, and number of emergency room visits remained significant between BP DEP+ and UP DEP+ respondents.

Subjects with self-reported bipolar depression sought care more often from a number of diverse healthcare resources than subjects with self-reported unipolar depression. These findings underscore the morbidity associated with bipolar depression.