•This study was to assess whether three symptomatically defined phenotypes of MDD, (core depression, neurovegetative of melancholia and anxiety), could be differentiated based on acylcarnitine ...profiles at baseline, after eight weeks of citalopram/escitalopram treatment.•The current data demonstrated that these phenotypes have distinct patterns of acylcarnitine levels at baseline and after eight weeks of antidepressant treatment.•These findings may help to develop a metabolomic profile of MDD patients with the aim of improving subtype classification of the MDD syndrome.
Acylcarnitines have important functions in mitochondrial energetics and β-oxidation, and have been implicated to play a significant role in metabolic functions of the brain. This retrospective study examined whether plasma acylcarnitine profiles can help biochemically distinguish the three phenotypic subtypes of major depressive disorder (MDD): core depression (CD+), anxious depression (ANX+), and neurovegetative symptoms of melancholia (NVSM+).
Depressed outpatients (n = 240) from the Mayo Clinic Pharmacogenomics Research Network were treated with citalopram or escitalopram for eight weeks. Plasma samples collected at baseline and after eight weeks of treatment with citalopram or escitalopram were profiled for short-, medium- and long-chain acylcarnitine levels using AbsoluteIDQ®p180-Kit and LC-MS. Linear mixed effects models were used to examine whether acylcarnitine levels discriminated the clinical phenotypes at baseline or eight weeks post-treatment, and whether temporal changes in acylcarnitine profiles differed between groups.
Compared to ANX+, CD+ and NVSM+ had significantly lower concentrations of short- and long-chain acylcarnitines at both baseline and week 8. In NVSM+, the medium- and long-chain acylcarnitines were also significantly lower in NVSM+ compared to ANX+. Short-chain acylcarnitine levels increased significantly from baseline to week 8 in CD+ and ANX+, whereas medium- and long-chain acylcarnitines significantly decreased in CD+ and NVSM+.
In depressed patients treated with SSRIs, β-oxidation and mitochondrial energetics as evaluated by levels and changes in acylcarnitines may provide the biochemical basis of the clinical heterogeneity of MDD, especially when combined with clinical characteristics.
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.
Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients ...having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM.
A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction.
The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the
(CUB complement C1r/C1s, Uegf, and Bmp1 domain containing protein 1) gene (rs6773435;
=7.12×10
). The variant allele was associated with improved cardiac function and decreased
transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis.
may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.
IMPORTANCE: Infection-associated immune activation and inflammation are increasingly recognized in the pathophysiology of bipolar disorder. OBJECTIVE: To determine whether antibodies to common ...infectious agents, including cytomegalovirus (CMV), Toxoplasma gondii, and measles, as well as the inflammatory marker C-reactive protein, in serum samples differ between patients with bipolar disorder and control individuals without bipolar disorder. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, antibody titers were measured in serum samples from 1207 patients with bipolar disorder and 745 controls that were obtained from biobanks with participating sites in Rochester and Minneapolis, Minnesota (n = 1537), and Cincinnati, Ohio (n = 415), from January 5, 2009, through May 12, 2014. A subset of case patients and controls from Minnesota were matched by age, sex, and educational level. Bipolar type, age at onset, and history of psychosis were assessed for case patients as well as current drug treatment at the time of blood sample obtainment from the biobank. Data were analyzed from February 5, 2018, to January 4, 2019. EXPOSURES: The CMV and T gondii antibodies with IgM titers were expressed as z scores and IgG titers dichotomized into seropositive and seronegative based on expected prevalence in the US population and further classified based on the joint CMV-positive/T gondii–negative IgG status, C-reactive protein z score, and drug treatments with antitoxoplasma activity. MAIN OUTCOMES AND MEASURES: Patients were stratified by bipolar disorder type I or type II, nonearly (>19 years of age) and early (≤19 years of age) onset, and history of psychosis during mania or no psychosis. RESULTS: Of 1207 patients with bipolar disorder (mean SD age, 43.2 15.1 years; 742 61.5% female), the CMV-positive/T gondii–negative IgG status was significantly higher (odds ratio OR, 1.33; 95% CI, 1.09-1.62; P = .004) compared with that in the 745 controls (mean SD age, 44.5 15.5 years; 444 59.6% female). The CMV-positive/T gondii–negative IgG status was associated with bipolar cases type I (OR, 1.41; 95% CI, 1.14-1.75; P = .001), nonearly age at onset (OR, 1.41; 95% CI, 1.16-1.72; P = .001), and history of manic psychosis (OR, 1.46; 95% CI, 1.13-1.88; P = .004). Patients with bipolar disorder who received drug treatment with antitoxoplasma activity (n = 272) had significantly lower T gondii IgM titers (median, 1.59; interquartile range, 1.30-2.07) compared with those (n = 900) who did not receive this treatment (median, 1.69; interquartile range, 1.35-2.25) (P = .03). CONCLUSIONS AND RELEVANCE: In this sample, increased long-term antibody response to CMV and decreased long-term antibody response to T gondii were associated with bipolar disorder and the subphenotypes of bipolar type I, nonearly disease onset, and manic psychosis. Further work appears to be needed to better understand genetic vs environmental disease risk and infection or immune activation contribution to overall disease pathogenesis with particular reference to disease onset.
•Negative and positive mood differentially impact alcohol use in males and females.•Previous research did not differentiate impact of mood states vs lifetime diagnoses.•This study confirmed positive ...association of mood with alcohol use in both sexes.•Yet, in alcoholic men, MDD correlated negatively with the frequency of alcohol use.•This difference should be accounted for in clinical practice and research.
We assessed the impact of comorbid depression and anxiety disorders as well as positive and negative emotional states on alcohol consumption in alcohol dependent men and women.
Per day alcohol consumption during 90 days before enrolment was assessed by the Time Line Follow Back (TLFB) in 287 men and 156 women meeting DSM-IV-TR criteria for alcohol dependence. Propensity to drink in negative/positive emotional states was assessed using the Inventory of Drug Taking Situations (IDTS). Psychiatric comorbidities, including major depressive disorder (MDD), substance-induced depression (SID), anxiety disorders (AnxD), or substance-induced anxiety (SIA) were identified by Psychiatric Research Interview of Substance and Mood Disorders (PRISM).
In the combined group, increased number of drinks per day and number of heavy drinking days correlated with increased IDTS scores (all p < 0.0001), while the lifetime history of MDD was associated with fewer drinking days (p = 0.045) but not average number of drinks per day. Male sex was associated with higher alcohol consumption per day (p < 0.0001), but not with the number of drinking days (p > 0.05). Lifetime MDD history was associated with less drinking days (p = 0.0084) and less heavy drinking days (p = 0.021) in alcohol dependent men, while current MDD was associated with higher alcohol use per day in alcohol dependent women (p = 0.044).
Our findings suggest that emotional states and lifetime MDD history have sex-specific impact on alcohol use in alcohol dependent men and women. The mechanisms underlying these findings and their relevance to treatment outcomes need to be examined in future studies.
Background and Purpose
Acamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was ...designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes.
Experimental Approach
We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3‐month follow‐up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics.
Key Results
Baseline plasma arginine, threonine, α‐aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics‐informed genome‐wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell‐derived forebrain astrocytes showed that a series of genes identified during the metabolomics‐informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes.
Conclusion and Implications
These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.
Lifetime history of major depressive disorder (MDD) has a sex-specific association with pretreatment alcohol consumption in patients with alcohol dependence. Here, we investigated the association of ...genetic load for MDD estimated using a polygenic risk score (PRS) with pretreatment alcohol consumption assessed with Timeline Follow Back in a sample of 287 men and 156 women meeting DSM-IV-TR criteria for alcohol dependence. Preferred drinking situations were assessed using the Inventory of Drug Taking Situations (IDTS). Linear models were used to test for association of normalized alcohol consumption measures with the MDD-PRS, adjusting for ancestry, age, sex, and number of days sober at baseline. We fit models both with and without adjustment for MDD history and alcohol-use-related PRSs as covariates. Higher MDD-PRS was associated with lower 90-day total alcohol consumption in men (β = −0.16, p = 0.0012) but not in women (β = 0.11, p = 0.18). The association of MDD-PRS with IDTS measures was also sex-specific: higher MDD-PRS was associated with higher propensity to drink in temptation-related situations in women, while the opposite (negative association)was found in men. MDD-PRS was not associated with lifetime MDD history in our sample, and adjustment for lifetime MDD and alcohol-related PRSs did not impact the results. Our results suggest that genetic load for MDD impacts pretreatment alcohol consumption in a sex-specific manner, which is similar to, but independent from, the effect of history of MDD. The clinical implications of these findings and contributing biological and psychological factors should be investigated in future studies.
•History of major depressive disorder has sex-specific association with alcohol use.•Genetic load for MDD was inversely associated with alcohol use in men but not women.•Genetic load for MDD inversely correlated with temptation-driven use in women and men.•MDD history and genetic load for MDD were associated with alcohol use independently.•Clinical implications of these findings and their mechanisms should be investigated.
Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to ...antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS,
= 529) and the International SSRI Pharmacogenomics Consortium (ISPC,
= 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at
< 0.05 across P
thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near
gene and (b) SSRI remission and neuroticism eight loci near
, and
genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.
Major depressive disorder (MDD) is a heterogeneous disease. Efforts to identify biomarkers for sub-classifying MDD and antidepressant therapy by genome-wide association studies (GWAS) alone have ...generally yielded disappointing results. We applied a metabolomics-informed genomic research strategy to study the contribution of genetic variation to MDD pathophysiology by assaying 31 metabolites, including compounds from the tryptophan, tyrosine, and purine pathways, in plasma samples from 290 MDD patients. Associations of metabolite concentrations with depressive symptoms were determined, followed by GWAS for selected metabolites and functional validation studies of the genes identified. Kynurenine (KYN), the baseline plasma metabolite that was most highly associated with depressive symptoms, was negatively correlated with severity of those symptoms. GWAS for baseline plasma KYN concentrations identified SNPs across the beta-defensin 1 (DEFB1) and aryl hydrocarbon receptor (AHR) genes that were cis-expression quantitative trait loci (eQTLs) for DEFB1 and AHR mRNA expression, respectively. Furthermore, the DEFB1 locus was associated with severity of MDD symptoms in a larger cohort of 803 MDD patients. Functional studies demonstrated that DEFB1 could neutralize lipopolysaccharide-stimulated expression of KYN-biosynthesizing enzymes in monocytic cells, resulting in altered KYN concentrations in the culture media. In addition, we demonstrated that AHR was involved in regulating the expression of enzymes in the KYN pathway and altered KYN biosynthesis in cell lines of hepatocyte and astrocyte origin. In conclusion, these studies identified SNPs that were cis-eQTLs for DEFB1 and AHR and, which were associated with variation in plasma KYN concentrations that were related to severity of MDD symptoms.
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