Ardesheer Talati

Children of Depressed Mothers 1 Year After the Initiation of Maternal Treatment: Findings From the STAR*D-Child Study

OBJECTIVE Maternal depression is a consistent and well-replicated risk factor for child psychopathology. The authors examined the changes in psychiatric symptoms and global functioning in children of depressed women 1 year following the initiation of treatment for maternal major depressive disorder. METHOD Participants were 1) 151 women with maternal major depression who were enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 2) their eligible offspring who, along with the mother, participated in the child STAR*D (STAR*D-Child) study (mother-child pairs: N=151). The STAR*D study was a multisite study designed to determine the comparative effectiveness and acceptability of various treatment options for adult outpatients with nonpsychotic major depressive disorder. The STAR*D-Child study examined children of depressed women at baseline and involved periodic follow-ups for 1 year after the initiation of treatment for maternal major depressive disorder to ascertain the following data: 1) whether changes in childrens psychiatric symptoms were associated with changes in the severity of maternal depression and 2) whether outcomes differed among the offspring of women who did and did not remit (mother-child pairs with follow-up data: N=123). Childrens psychiatric symptoms in the STAR*D-Child study were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), and maternal depression severity in the STAR*D study was assessed by an independent clinician, using the 17-item Hamilton Depression Rating Scale (HAM-D). RESULTS During the year following the initiation of treatment, maternal depression severity and childrens psychiatric symptoms continued to decrease over time. Decreases in the number of childrens psychiatric symptoms were significantly associated with decreases in maternal depression severity. When childrens outcomes were examined separately, a statistically significant decrease in symptoms was evident in the offspring of women who remitted early (i.e., within the first 3 months after the initiation of treatment for maternal depression) or late (i.e., over the 1-year follow-up interval) but not in the offspring of nonremitting women. CONCLUSIONS Continued efforts to treat maternal depression until remission is achieved are associated with decreased psychiatric symptoms and improved functioning in the offspring.

Functional Specialization within the Medial Frontal Gyrus for Perceptual Go/No-Go Decisions Based on What, When, and Where Related Information: An fMRI Study

Cortical systems engaged during executive and volitional functions receive and integrate input from multiple systems. However, these integration processes are not well understood. In particular, it is not known whether these input pathways converge or remain segregated at the executive levels of cortical information processing. If unilateral information streams are conserved within structures that serve high-level executive functions, then the functional organization within these structures would predictably be similarly organized. If, however, unilateral input information streams are integrated within executive-related structures, then activity patterns will not necessarily reflect lower organizations. In this study, subjects were imaged during the performance of a perceptual go/nogo task for which instructions were based on spatial (where), temporal (when), or object (what) stimulus features known to engage unilateral processing streams, and the expected hemispheric biases were observed for early processing areas. For example, activity within the inferior and middle occipital gyri, and the middle temporal gyrus, during the what and when tasks, was biased toward the left hemisphere, and toward the right hemisphere during the where task. We discover a similar lateralization within the medial frontal gyrus, a region associated with high-level executive functions and decision-related processes. This lateralization was observed regardless of whether the response was executed or imagined, and was demonstrated in multiple sensory modalities. Although active during the go/no-go task, the cingulate gyrus did not show a similar lateralization. These findings further differentiate the organizations and functions of the medial frontal and cingulate executive regions, and suggest that the executive mechanisms operative within the medial frontal gyrus preserve fundamental aspects of input processing streams.

Panic disorder is associated with the serotonin transporter gene ( SLC6A4 ) but not the promoter region (5-HTTLPR)

Panic disorder (PD) and social anxiety disorder (SAD) are moderately heritable anxiety disorders. We analyzed five genes, derived from pharmacological or translational mouse models, in a new case–control study of PD and SAD in European Americans: (1) the serotonin transporter (SLC6A4), (2) the serotonin receptor 1A, (3) catechol-O-methyltransferase, (4) a regulator of g-protein signaling and (5) the gastrin-releasing peptide receptor. Cases were interviewed using the schedule for affective disorders and schizophrenia and were required to have a probable or definite lifetime diagnosis of PD (N=179), SAD (161) or both (140), with first onset by age 31 and a family history of anxiety. Final diagnoses were determined using the best estimate procedure, blind to genotyping data. Controls were obtained from the National Institute of Mental Health Human Genetics Initiative; only subjects above 25 years of age who screened negative for all psychiatric symptoms were included (N=470). A total of 45 single nucleotide polymorphisms were successfully genotyped over the five selected genes using Applied Biosystems SNPlex protocol. SLC6A4 provided strong and consistent evidence of association with the PD and PD+SAD groups, with the most significant association in both groups being at rs140701 (χ2=10.72, P=0.001 with PD and χ2=8.59, P=0.003 in the PD+SAD group). This association remained significant after multiple test correction. Those carrying at least one copy of the haplotype A-A-G constructed from rs3794808, rs140701 and rs4583306 have 1.7 times the odds of PD than those without the haplotype (95% confidence interval: 1.2–2.3). The SAD only group did not provide evidence of association, suggesting a PD-driven association. The findings remained after adjustment for age and sex, and there was no evidence that the association was due to population stratification. The promoter region of the gene, 5-HTTLPR, did not provide any evidence of association, regardless of whether analyzed as a triallelic or biallelic locus, nor did any of the other four candidate genes tested. Our findings suggest that the serotonin transporter gene may play a role in PD; however, the findings require replication. Future studies should attend to the entire genetic region rather than the promoter.

Gray Matter Abnormalities in Social Anxiety Disorder: Primary, Replication, and Specificity Studies

BACKGROUND Despite increasing evidence that neuroanatomical abnormalities underlie pathological anxiety, social anxiety disorder (SAD)-although among the most common of anxiety disorders-has received little attention. With magnetic resonance imaging, we: 1) examined gray matter (GM) differences between generalized SAD and healthy control groups; 2) retested the findings in an independent clinical sample; and 3) tested for specificity by contrasting the SAD group to a separate group of panic disorder (PD) subjects. METHODS The primary SAD group (n = 16) was required to meet DSM-IV criteria for SAD, with onset by age 30 years; control subjects (n = 20) had no lifetime history of anxiety. The replication sample included 17 generalized SAD and 17 control subjects. The PD comparison group (n = 16) was required to have no lifetime SAD. Images were acquired on a 1.5-Tesla GE Signa magnetic resonance imaging scanner with a three-dimensional T1-weighted spoiled gradient recalled pulse sequence. Morphological differences were determined with voxel-based morphometry, in SPM8. RESULTS After adjusting for age, gender, and total intracranial volume, SAD (as compared with control) subjects had greater GM in the left parahippocampal and middle occipital, and bilateral supramarginal and angular cortices, and left cerebellum; and lower GM in bilateral temporal poles and left lateral orbitofrontal cortex. Cerebellar, parahippocampal, and temporal pole differences were observed in both samples, survived whole brain corrections, and were not observed in the PD group, pointing to relative specificity to SAD. CONCLUSIONS These findings parallel the functional literature on SAD and suggest structural abnormalities underlying the functional disturbances.

Temperament among offspring at high and low risk for depression

The purpose of this study was to examine relationships between parental depression, offspring temperament, and offspring major depressive disorder (MDD), and to determine whether difficult temperament, as measured by the Dimensions of Temperament Survey (DOTS), mediates the relation between parental MDD and offspring MDD. Offspring (n=169) of depressed or never depressed parents were followed over approximately 20 years and were blindly assessed up to 4 times (Waves 1 to 4) using semi-structured interviews. Offspring completed the DOTS at the time of first or second assessment. The results showed: (1) high-risk offspring with one or more depressed parent were significantly more likely than offspring with neither parent depressed to have a difficult temperament; (2) offspring with a difficult temperament were more than twice as likely as those with an easy temperament to develop a MDD; and (3) difficult temperament explained more than 10% of the association between parental depression and new onsets of MDD in offspring. The findings suggest that offspring temperament is associated with development of MDD and that difficult temperament at least partially mediates the relationship between parental depression and offspring depression. When identifying those at greatest risk for MDD, measures of temperament could serve as a useful supplement to family psychiatric history of MDD.

Association of a polyadenylation polymorphism in the serotonin transporter and panic disorder.

BACKGROUND Genetic markers in the serotonin transporter are associated with panic disorder (PD). The associated polymorphisms do not include the serotonin transporter-linked polymorphic region and display no obvious functional attributes. A common polymorphism (rs3813034) occurs in one of the two reported polyadenylation signals for the serotonin transporter and is in linkage disequilibrium with the PD-associated markers. If functional, rs3813034 might be the risk factor that explains the association of the serotonin transporter and PD. METHODS Quantitative polymerase chain reaction on human brain samples (n = 65) and lymphoblast cultures (n = 71) was used to test rs3813034 for effects on expression of the polyadenylation forms of the serotonin transporter. rs3813034 was also tested for association in a sample of PD cases (n = 307) and a control sample (n = 542) that has similar population structure. RESULTS The balance of the two polyadenylation forms of the serotonin transporter is associated with rs3813034 in brain (p < .001) and lymphoblasts (p < .001). The balance of the polyadenylation forms is also associated with gender in brain only (p < .05). Association testing of rs3813034 in PD identified a significant association (p = .0068) with a relative risk of 1.56 and 1.81 for the heterozygous and homozygous variant genotypes, respectively. CONCLUSIONS rs3813034 is a functional polymorphism in the serotonin transporter that alters the balance of the two polyadenylation forms of the serotonin transporter. rs3813034 is a putative risk factor for PD and other behavioral disorders that involve dysregulation of serotonergic neurotransmission.

Translational Epidemiology in Psychiatry: Linking Population to Clinical and Basic Sciences

Translational research generally refers to the application of knowledge generated by advances in basic sciences research translated into new approaches for diagnosis, prevention, and treatment of disease. This direction is called bench-to-bedside. Psychiatry has similarly emphasized the basic sciences as the starting point of translational research. This article introduces the term translational epidemiology for psychiatry research as a bidirectional concept in which the knowledge generated from the bedside or the population can also be translated to the benches of laboratory science. Epidemiologic studies are primarily observational but can generate representative samples, novel designs, and hypotheses that can be translated into more tractable experimental approaches in the clinical and basic sciences. This bedside-to-bench concept has not been explicated in psychiatry, although there are an increasing number of examples in the research literature. This article describes selected epidemiologic designs, providing examples and opportunities for translational research from community surveys and prospective, birth cohort, and family-based designs. Rapid developments in informatics, emphases on large sample collection for genetic and biomarker studies, and interest in personalized medicine--which requires information on relative and absolute risk factors--make this topic timely. The approach described has implications for providing fresh metaphors to communicate complex issues in interdisciplinary collaborations and for training in epidemiology and other sciences in psychiatry.

Decoding Unattended Fearful Faces with Whole-Brain Correlations: An Approach to Identify Condition-Dependent Large-Scale Functional Connectivity

Processing of unattended threat-related stimuli, such as fearful faces, has been previously examined using group functional magnetic resonance (fMRI) approaches. However, the identification of features of brain activity containing sufficient information to decode, or “brain-read”, unattended (implicit) fear perception remains an active research goal. Here we test the hypothesis that patterns of large-scale functional connectivity (FC) decode the emotional expression of implicitly perceived faces within single individuals using training data from separate subjects. fMRI and a blocked design were used to acquire BOLD signals during implicit (task-unrelated) presentation of fearful and neutral faces. A pattern classifier (linear kernel Support Vector Machine, or SVM) with linear filter feature selection used pair-wise FC as features to predict the emotional expression of implicitly presented faces. We plotted classification accuracy vs. number of top N selected features and observed that significantly higher than chance accuracies (between 90–100%) were achieved with 15–40 features. During fearful face presentation, the most informative and positively modulated FC was between angular gyrus and hippocampus, while the greatest overall contributing region was the thalamus, with positively modulated connections to bilateral middle temporal gyrus and insula. Other FCs that predicted fear included superior-occipital and parietal regions, cerebellum and prefrontal cortex. By comparison, patterns of spatial activity (as opposed to interactivity) were relatively uninformative in decoding implicit fear. These findings indicate that whole-brain patterns of interactivity are a sensitive and informative signature of unattended fearful emotion processing. At the same time, we demonstrate and propose a sensitive and exploratory approach for the identification of large-scale, condition-dependent FC. In contrast to model-based, group approaches, the current approach does not discount the multivariate, joint responses of multiple functional connections and is not hampered by signal loss and the need for multiple comparisons correction.

Maternal Smoking During Pregnancy and Bipolar Disorder in Offspring

OBJECTIVE Maternal smoking during pregnancy is associated with a number of adverse externalizing outcomes for offspring from childhood to adulthood. The relationship between maternal smoking and bipolar disorder in offspring, which includes externalizing symptoms among its many manifestations, has not been investigated in depth. The authors examined whether offspring exposed to maternal smoking in utero would be at increased lifetime risk for bipolar disorder after accounting for other factors related to maternal smoking. METHOD Individuals with bipolar disorder (N=79) were ascertained from the birth cohort of the Child Health and Development Study. Case subjects were identified by a combination of clinical, database, and direct mailing sources; all case subjects were directly interviewed and diagnosed using DSM-IV criteria. Comparison subjects (N=654) were matched to case subjects on date of birth (±30 days), sex, membership in the cohort at the time of illness onset, and availability of maternal archived sera. RESULTS After adjusting for potential confounders, offspring exposed to in utero maternal smoking exhibited a twofold greater risk for bipolar disorder (odds ratio=2.014, 95% confidence interval=1.48-2.53, p=0.01). The associations were noted primarily among bipolar offspring without psychotic features. CONCLUSIONS Prenatal tobacco exposure may be one suspected cause of bipolar disorder. However, it will be necessary to account for other unmeasured familial factors before causal teratogenic effects can be suggested.

Changing relationships between smoking and psychiatric disorders across twentieth century birth cohorts: clinical and research implications

As the risks of tobacco use become recognized and smoking becomes stigmatized, new smokers may be increasingly driven to smoke by biological or genetic vulnerabilities rather than social desirability. Given that genetic risk for deviant proneness is shared across other psychiatric and addictive disorders, we predicted that as rates of smoking decreased through the latter half of the twentieth century, associations between smoking and psychopathology would increase. Participants (N=25 412) from a large US study—the National Epidemiologic Survey on Alcohol and Related Conditions, NESARC—were interviewed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule – DSM-IV Version (AUDADIS-IV) and classified into one of five birth cohort decades (1940s to 1980s) and three smoking history (nonsmokers, never-dependent smokers and ever-dependent smokers) groups. We found that the prevalence of smoking decreased across the five birth cohorts, but associations of smoking with drug and AUDs, attention-deficit hyperactivity disorder, bipolar disorder and antisocial personality disorder, each increased monotonically in more recently born cohorts, even after adjusting for concurrent demographic and socioeconomic changes. For drug and AUDs, increases were observed among smokers both with and without a history of nicotine dependence; for other outcomes, increases were entirely driven by nicotine-dependent smokers. Findings suggest that smokers in more recent cohorts have disproportionately high psychiatric vulnerability, and may benefit from greater mental health screenings. Differentiating between casual and dependent smokers may further help prioritize those at greatest risk. Researchers should also be aware of potential variation in psychiatric comorbidity based on cohort of birth when defining groups of smokers, to minimize confounding.