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Cáceda, R., Bush, K., James, G. A., Stowe, Z. N., & Kilts, C. D. (2018). Modes of Resting Functional Brain Organization Differentiate Suicidal Thoughts and Actions: A Preliminary Study. The Journal of Clinical Psychiatry, 79(4).


Objective: A major target in suicide prevention is interrupting the progression from suicidal thoughts to action. Use of complex algorithms in large samples has identified individuals at very high risk for suicide. We tested the ability of data-driven pattern classification analysis of brain functional connectivity to differentiate recent suicide attempters from patients with suicidal ideation.

Methods: We performed a cross-sectional study using resting-state functional magnetic resonance imaging in depressed inpatients and outpatients of both sexes recruited from a university hospital between March 2014 and June 2016: recent suicide Attempters within 3 days of an attempt (n = 10), Suicidal Ideators (n = 9), Depressed Non-Suicidal Controls (n =17), and Healthy Controls (n = 18). All depressed patients fulfilled DSM-IV-TR criteria for major depressive episode and either major depressive disorder, bipolar disorder, or depression not otherwise specified. A subset of suicide attempters (n = 7) were rescanned within 7 days. We used a support vector machine data-driven neural pattern classification analysis of resting-state functional connectivity to characterize recent suicide attempters and then tested the classifier’s specificity.

Results: A binary classifier trained to discriminate patterns of resting-state functional connectivity robustly differentiated Suicide Attempters from Suicidal Ideators (mean accuracy = 0.788, signed rank test: P = .002; null hypothesis: area under the curve = 0.5), with distinct functional connectivity between the default mode and the limbic, salience, and central executive networks. The classifier did not discriminate stable Suicide Attempters from Suicidal Ideators (mean accuracy = 0.58, P = .33) or presence from absence of lifetime suicidal behavior (mean accuracy = 0.543, P = .348) and was not improved by modeling clinical variables (mean accuracy = 0.736, P = .002).

Conclusions: Measures of intrinsic brain organization may have practical value as objective measures of suicide risk and its underlying mechanisms. Further incorporation of serum or cognitive markers and use of a prospective study design are needed to validate and refine the clinical relevance of this candidate biomarker of suicide risk.

Steele, J. S., Bush, K., Stowe, Z. N., James, G. A., Smitherman, S., Kilts, C. D., & Cisler, J. (2018). Implicit emotion regulation in adolescent girls: An exploratory investigation of Hidden Markov Modeling and its neural correlates. PLOS ONE, 13(2), e0192318.


Numerous data demonstrate that distracting emotional stimuli cause behavioral slowing (i.e. emotional conflict) and that behavior dynamically adapts to such distractors. However, the cognitive and neural mechanisms that mediate these behavioral findings are poorly understood. Several theoretical models have been developed that attempt to explain these phenomena, but these models have not been directly tested on human behavior nor compared. A potential tool to overcome this limitation is Hidden Markov Modeling (HMM), which is a computational approach to modeling indirectly observed systems. Here, we administered an emotional Stroop task to a sample of healthy adolescent girls (N = 24) during fMRI and used HMM to implement theoretical behavioral models. We then compared the model fits and tested for neural representations of the hidden states of the most supported model. We found that a modified variant of the model posited by Mathews et al. (1998) was most concordant with observed behavior and that brain activity was related to the model-based hidden states. Particularly, while the valences of the stimuli themselves were encoded primarily in the ventral visual cortex, the model-based detection of threatening targets was associated with increased activity in the bilateral anterior insula, while task effort (i.e. adaptation) was associated with reduction in the activity of these areas. These findings suggest that emotional target detection and adaptation are accomplished partly through increases and decreases, respectively, in the perceived immediate relevance of threatening cues and also demonstrate the efficacy of using HMM to apply theoretical models to human behavior.

House, S. J., Coker, J. L., & Stowe, Z. N. (2016). Perinatal Substance Abuse: At the Clinical Crossroads of Policy and Practice. The American Journal of Psychiatry, 173(11), 1077–1080.


Although much of the focus in treatment of psychiatric illness in pregnancy has been on mood disorders, the prevalence of substance abuse rivals that of major depressive disorder during pregnancy (1). A survey of drug use and health indicated that 5.4% of pregnant women ages 15–44 used illicit drugs (marijuana, cocaine, heroin, hallucinogens, inhalants, or non-medical use of prescription medications) at the time of the study (2). Illicit drug use occurred more frequently during the first and second trimesters than during the third trimester, and it was highest among respondents ages 15–17 (2). However, the clinical identification of substance abuse during pregnancy largely relies on patient report, and the rigor and documentation of screening varies. Despite discordant data, evidence supports an increased potential for adverse effects associated with prenatal exposure to both licit and illicit substances (3).The long-term consequences of neonatal abstinence syndrome (NAS) are not well characterized, however. Prescription medication abuse represents an unknown hazard for the offspring, subject to scrutiny under the legal statutes for substance abuse in the perinatal period. The prevalence of substance abuse, combined with its possible consequences, has led jurisdictions to adopt a variety of approaches in dealing with this problem. State supreme court rulings in Alabama, Mississippi, and New Jersey (4–7), along with legislation in Tennessee (8), spurred significant debate regarding the criminalization of perinatal substance abuse. Practitioners should be aware of their districts’ legal requirements involving perinatal substance abuse. The interface of legal issues and clinical care for this population has led many medical societies to publish position statements on this issue.

Perinatal Substance Abuse-At the Clinical Crossroads of Policy and Practice

Schroeder, J. W., Smith, A. K., Brennan, P. A., Conneely, K. N., Kilaru, V., Knight, B. T., … Stowe, Z. N. (2012). DNA methylation in neonates born to women receiving psychiatric care. Epigenetics, 7(4), 409–414.


Prenatal exposure both to maternal psychiatric illness and psychiatric medication has been linked with adverse child outcomes that affect physiological, emotional and psychiatric development. Studies suggest that epigenetic mechanisms, such as DNA methylation, may facilitate these effects. In this report, we explore the association between maternal psychiatric illness and treatment during pregnancy and neonatal DNA methylation patterns in a prospectively-characterized clinical cohort of 201 dyads. Associations between the percent of umbilical cord blood DNA methylated at 27,578 CpG sites and maternal psychiatric diagnosis, symptoms and antidepressant use were evaluated by fitting a separate linear mixed effects model for each CpG site. There were no significant changes in neonatal DNA methylation attributable to maternal psychiatric diagnosis or depressive symptoms during pregnancy. Exposure to an antidepressant medication was associated with differential methylation of CpG sites in TNFRSF21 and CHRNA2 (false discovery rate < 0.05), but the average difference in methylation for both CpG sites was less than 3% between each group. The results were not specific to type of antidepressant or duration of the exposure. This study suggests that there are no large effects of maternal psychiatric illness, depressive symptoms or prenatal exposure to antidepressants on neonatal DNA methylation. Delineation of the influence of maternal psychiatric illness and pharmacological exposures on the developing fetuses has critical implications for clinical care during pregnancy.

DNA methylation in neonates PDF

Cohen, L. S., Altshuler, L. L., Harlow, B. L., Nonacs, R., Newport, D. J., Viguera, A. C., … Stowe, Z. N. (2006). Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA, 295(5), 499–507.


Context Pregnancy has historically been described as a time of emotional well-being, providing “protection” against psychiatric disorder. However, systematic delineation of risk of relapse in women who maintain or discontinue pharmacological treatment during pregnancy is necessary.

Objective To describe risk of relapse in pregnant women who discontinued antidepressant medication proximate to conception compared with those who maintained treatment with these medications.

Design, Setting, and Patients A prospective naturalistic investigation using longitudinal psychiatric assessments on a monthly basis across pregnancy; a survival analysis was conducted to determine time to relapse of depression during pregnancy. A total of 201 pregnant women were enrolled between March 1999 and April 2003 from 3 centers with specific expertise in the treatment of psychiatric illness during pregnancy. The cohort of women was recruited from (1) within the hospital clinics, (2) self-referral via advertisements and community outreach detailing the study, and (3) direct referrals from the community. Participants were considered eligible if they (1) had a history of major depression prior to pregnancy, (2) were less than 16 weeks’ gestation, (3) were euthymic for at least 3 months prior to their last menstrual period, and (4) were currently or recently (<12 weeks prior to last menstrual period) receiving antidepressant treatment. Of the 201 participants, 13 miscarried, 5 electively terminated their pregnancy, 12 were lost to follow-up prior to completion of pregnancy, and 8 chose to discontinue participation in the study.

Main Outcome Measure Relapse of major depression defined as fulfilling Structured Clinical Interview for DSM-IV [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition] Diagnosis (SCID) criteria.

Results Among the 201 women in the sample, 86 (43%) experienced a relapse of major depression during pregnancy. Among the 82 women who maintained their medication throughout their pregnancy, 21 (26%) relapsed compared with 44 (68%) of the 65 women who discontinued medication. Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy compared with women who maintained their medication (hazard ratio, 5.0; 95% confidence interval, 2.8-9.1; P<.001).

Conclusions Pregnancy is not “protective” with respect to risk of relapse of major depression. Women with histories of depression who are euthymic in the context of ongoing antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation.

Relapse of MDD during pregnancy PDF