Lisa Halberstadt

Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4.

Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50–60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD=4.59, P=2.1 × 10−6, at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0–2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.

Cognitive Vulnerability to Depression and Lifetime History of Axis I Psychopathology: A Comparison of Negative Cognitive Styles (CSQ) and Dysfunctional Attitudes (DAS)

The goal of this study was to “unpack” the “generic” cognitive vulnerability employed in the retrospective behavioral high-risk design of Alloy and colleagues (2000), one of the major publications emanating from the Cognitive Vulnerability to Depression (CAD) Project to date. To this end, we used a retrospective behavioral high-risk design with a new sample of unselected undergraduates and examined the unique association between lifetime history of clinically significant depression as well as other Axis I disorders (e.g., anxiety disorders, substance abuse disorders) and both dysfunctional attitudes (DAS, featured in Beck’s theory) and negative cognitive styles (CSQ, featured in hopelessness theory). We present results supporting the cognitive vulnerability factor featured in the hopelessness theory and the construct validity of the CSQ. Negative cognitive styles were more strongly and consistently associated with lifetime history of Research Diagnostic Criteria (RDC) major depression and hopelessness depression than were dysfunctional attitudes. These results suggest that negative cognitive styles, as assessed by the CSQ, were a potent component of the “generic” cognitive vulnerability effect in Alloy and associates’ (2000) retrospective behavioral high-risk design. Interestingly, negative cognitive styles also were significantly associated with a participant having had a past RDC anxiety diagnosis. Thus, consistent with past research, our results suggest that negative cognitive styles and dysfunctional attitudes are distinct constructs as measured by the CSQ and DAS, respectively. Of further interest, gender differences in depression were obtained with college women in our study exhibiting significantly greater lifetime history of RDC major depression than college men.

Blue again: Perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression

Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. If the homeostatic mechanisms regulating monoamines are functioning properly in these patients, then oppositional tolerance should develop with prolonged antidepressant medication (ADM) therapy. Oppositional tolerance refers to the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM. We test this prediction by conducting a meta-analysis of ADM discontinuation studies. We find that the risk of relapse after ADM discontinuation is positively associated with the degree to which ADMs enhance serotonin and norepinephrine in prefrontal cortex, after controlling for covariates. The results are consistent with oppositional tolerance, and provide no evidence of malfunction in the monoaminergic regulatory mechanisms in patients meeting current diagnostic criteria for MDD. We discuss the evolutionary and clinical implications of our findings.

The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history.

BACKGROUND This article is the first report of the Irish Affected Sib Pair Study of Alcohol Dependence, whose goal is to detect the genomic location of susceptibility loci for alcohol dependence (AD). This article describes phenotypic characteristics of the probands, siblings, and parents included in the sample and examines agreement among different sources of diagnostic information, including the validity of family history (FH) assessment. METHODS Structured diagnostic interviews were conducted with 1414 individuals from 591 families ascertained in Ireland. AD was assessed among 1201 probands and affected siblings with use of the Semi-Structured Assessment for the Genetics of Alcoholism and among 213 parents with use of a modified version of the Structured Clinical Interview for DSM. Probands and siblings were also assessed for drinking history, comorbid disorders, and other clinical characteristics. FH reports based on FH-Research Diagnostic Criteria were obtained for 1113 of these individuals as well as for 3652 first-degree relatives who were not interviewed. RESULTS Sample characteristics confirm the severity of AD among the affected individuals. Agreement between FH ratings and diagnoses based on direct interviews was high for both parent-offspring and sibling-sibling comparisons (e.g., positive and negative predictive values > 80% for a range of cutoffs). Agreement among individuals about their family members was also high for a single item (1 month or more of drinking problems, tetrachoric r = 0.86-0.98), the total number of DSM-IV AD symptoms (polychoric r = 0.86-0.96), and classifications based on a range of cutoffs (kappa = 0.75-0.80). Use of multiple informants improved classification accuracy only slightly (6-10%). CONCLUSIONS The authors successfully collected data for a large sample of affected sibling pairs for molecular genetic analysis of AD. Individuals with AD were able to provide accurate evaluations of alcoholism symptoms in their parents and adult siblings. A single screening item performed nearly as well as the full scale. Collecting information from multiple informants may not be cost effective for the gain in predictive accuracy. FH information collected from affected informants can be a valuable source of diagnostic information for family studies of alcoholism.

Spit for Science: launching a longitudinal study of genetic and environmental influences on substance use and emotional health at a large US university.

Finding genes involved in complex behavioral outcomes, and understanding the pathways by which they confer risk, is a challenging task, necessitating large samples that are phenotypically well characterized across time. We describe an effort to create a university-wide research project aimed at understanding how genes and environments impact alcohol use and related substance use and mental health outcomes across time in college students. Nearly 70% of the incoming freshman class (N = 2715) completed on-line surveys, with 80% of the students from the fall completing spring follow-ups. 98% of eligible participants also gave DNA. The participants closely approximated the university population in terms of gender and racial/ethnic composition. Here we provide initial results on alcohol use outcomes from the first wave of the sample, as well as associated predictor variables. We discuss the potential for this kind of research to advance our understanding of genetic and environment influences on substance use and mental health outcomes.

Schematic Processing: A Comparison of Clinically Depressed, Dysphoric, and Nondepressed College Students

Reformulations of Beck’s theory (e.g., Dykman et al. J Pers Social Psychol 56:431–445, 1989) propose that depressed and nondepressed people are equally likely to use schematic processing to interpret information. The few studies to test this hypothesis have had methodological shortcomings. Past studies have not included a clinically depressed sample and have failed to assess a full range of potential biases (negative, neutral, and positive). To address these limitations, a recognition-of-information task was administered to clinically depressed, dysphoric, and nondepressed college students. Clinically depressed participants were significantly more likely than nondepressed participants to generate negative interpretations of a self-relevant ambiguous story. Clinically depressed participants also were more likely than both dysphoric and nondepressed participants to refute positive interpretations of the story. However, consistent with reformulations of Beck’s theory, dysphoric participants and nondepressed participants also tended to “go beyond” the information given in the story. Indeed, all three participant groups were equally biased in their interpretations. The difference among the groups was in the direction (negative vs. positive) and the heterogeneity of the biases.

Do reasons for major depression act as causes

We make sense of human behavior using reasons, which produce understanding via a subjective empathy-based first-person perspective and causes, which leads to explanations utilizing objective facts about the world assessed scientifically. We evaluate the common sense hypothesis that for episodes of major depression (MD), reasons act as causes. That is, individuals who have highly understandable depressive episodes will have, on average, fewer objective scientifically validated causes than those who have un-understandable episodes. The understandability of a MD as defined by the Diagnostic and Statistical Manual, 4th Edition (DSM IV) experienced in the past year in 630 personally interviewed twins from a population-based registry was rated, with high reliability, from rich contextual information. We predicted, from these understandability ratings, via linear and logistic regression, 12 validated risk factors for MD reflecting genetic and long-term environmental liability. No significant association was observed between 11 of these indices and the understandability of the depressive episode. The only significant finding—higher cotwin risk for MD associated with greater understandability—was opposite that predicted by the reasons-as-causes hypothesis. Our results do not support the hypothesis that reasons for MD act as causes. These findings, unlikely to result from low power, may be explicable from an empirical and/or philosophical perspective. Our results are, however, consistent with ‘the trap of meaning’ hypothesis, which suggests that understanding does not equal explanation and that while reasons may be critical to help us empathize with our patients, they are unreliable indices of objective risk factors for illness.

Stress‐Generative Effects of Posttraumatic Stress Disorder: Transactional Associations Between Posttraumatic Stress Disorder and Stressful Life Events in a Longitudinal Sample

Longitudinal studies have demonstrated transactional associations between psychopathology and stressful life events (SLEs), such that psychopathology predicts the occurrence of new SLEs, and SLEs in turn predict increasing symptom severity. The association between posttraumatic stress disorder (PTSD), specifically, and stress generation remains unclear. This study used temporally sequenced data from 116 veterans (87.9% male) to examine whether PTSD symptoms predicted new onset SLEs, and if these SLEs were associated with subsequent PTSD severity. The SLEs were objectively rated, using a clinician-administered interview and consensus-rating approach, to assess the severity, frequency, and personal dependence (i.e., if the event was due to factors that were independent of or dependent on the individual) of new-onset SLEs. A series of mediation models were tested, and results provided evidence for moderated mediation whereby baseline PTSD severity robustly predicted personally dependent SLEs, B = 0.03, p = .006, and dependent SLEs predicted increases in follow-up PTSD symptom severity, B = -0.04, p = .003, among participants with relatively lower baseline PTSD severity. After we controlled for baseline PTSD severity, personality traits marked by low constraint (i.e., high impulsivity) were also associated with an increased number of dependent SLEs. Our results provide evidence for a stress-generative role of PTSD and highlight the importance of developing interventions aimed at reducing the occurrence of personally dependent stressors.