Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis.

BACKGROUND: 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. METHODS: 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. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 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. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

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.

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.

Genetic predisposition to major depressive disorder differentially impacts alcohol consumption and high-risk drinking situations in men and women with alcohol use disorder.

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 (ß = -0.16, p = 0.0012) but not in women (ß = 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.

Patient Satisfaction and Recommendations for Delivering a Group-Based Intensive Outpatient Program via Telemental Health During the COVID-19 Pandemic: Cross-sectional Cohort Study.

BACKGROUND: Although group-based intensive outpatient programs (IOPs) are a level of care commonly utilized by adults with serious mental illness, few studies have examined the acceptability of group-based IOPs that required rapid transition to a telemental health (TMH) format during the COVID-19 pandemic. OBJECTIVE: The aim of this study was to evaluate patient satisfaction and future recommendations for a group-based IOP that was transitioned to a TMH format during the COVID-19 pandemic. METHODS: A 17-item patient satisfaction questionnaire was completed by patients at discharge and covered 3 areas: IOP TMH satisfaction, future recommendations, and video technology challenges. Descriptive and content analyses were conducted for the quantitative and open-ended questions, respectively. RESULTS: A total of 76 patients completed the program in 2020. A subset of patients (n=40, 53%) responded to the survey at program discharge. The results indicated that the patients were satisfied overall with the TMH program format; 50% (n=20) of the patients preferred the program continue offering the TMH format, and the rest preferred returning to in-person formats after the pandemic. The patients indicated the elements of the program that they found most valuable and provided recommendations for future program improvement. CONCLUSIONS: Overall, adults with serious mental illness reported high satisfaction with the group-based IOP delivered via TMH. Health care systems may want to consider offering both TMH and in-person formats regardless of the state of the pandemic. Patients' feedback on future improvements should be considered to help ensure long-term success.

Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study.

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.

Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on ß-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to ß-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.

Acylcarnitine metabolomic profiles inform clinically-defined major depressive phenotypes.

BACKGROUND: Acylcarnitines have important functions in mitochondrial energetics and ß-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+). METHODS: 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. RESULTS: 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+. CONCLUSIONS: In depressed patients treated with SSRIs, ß-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.

Sex-specific association of depressive disorder and transient emotional states with alcohol consumption in male and female alcoholics.

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Association of Cytomegalovirus and Toxoplasma gondii Antibody Titers With Bipolar Disorder.

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.

Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics.

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.

Mapping depression rating scale phenotypes onto research domain criteria (RDoC) to inform biological research in mood disorders.

BACKGROUND: Substantial research progress can be achieved if available clinical datasets can be mapped to the National Institute of Mental Health Research-Domain-Criteria (RDoC) constructs. This mapping would allow investigators to both explore more narrowly defined clinical phenotypes and the relationship of these phenotypes to biological markers and clinical outcomes approximating RDoC criteria. METHODS: Using expert review and consensus, we defined four major depression phenotypes based on specific RDoC constructs. Having matched these constructs to individual items from the Hamilton Depression Rating Scale and Quick Inventory of Depressive Symptomatology, we identified subjects meeting criteria for each of these phenotypes from two large clinical trials of patients treated for major depression. In a post hoc analysis, we evaluated the overall treatment response based on the phenotypes: Core Depression (CD), Anxiety (ANX), and Neurovegetative Symptoms of Melancholia (NVSM) and Atypical Depression (NVSAD). RESULTS: The phenotypes were prevalent (range 10.5-52.4%, 50% reduction range 51.9-82.9%) and tracked with overall treatment response. Although the CD phenotype was associated with lower rates of remission in both cohorts, this was mainly driven by baseline symptom severity. However, when controlling for baseline severity, patients with the ANX phenotype had a significantly lower rate of remission. LIMITATIONS: The lack of replication between the studies of the phenotypes' treatment prediction value reflects important variability across studies that may limit generalizability. CONCLUSION: Further work evaluating biological markers associated with these phenotypes is needed for further RDoC concept development.

Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder.

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, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 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 p < 0.05 across PT 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 YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 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.

Gender-specific effects of comorbid depression and anxiety on the propensity to drink in negative emotional states.

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 (ß = 6.6, P = 0.013) and AnxD (ß = 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 (ß = 7.9, P = 0.009) compared with females (ß = -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.