Laura Michele Hack

All Publications

• Opioids Diminish the Placebo Antidepressant Response: A Post Hoc Analysis of a Randomized Controlled Ketamine Trial. medRxiv : the preprint server for health sciences Lii, T. R., Flohr, J. R., Okada, R. L., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2024

  Abstract

  The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses.This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment.The analysis showed that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, baseline pain intensity, and ethnicity. Additionally, there was negligible correlation between postoperative pain intensity and depression severity.This analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies.Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

  View details for DOI 10.1101/2024.09.24.24314243

  View details for PubMedID 39399033

  View details for PubMedCentralID PMC11469457

• Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety. Nature medicine Tozzi, L., Zhang, X., Pines, A., Olmsted, A. M., Zhai, E. S., Anene, E. T., Chesnut, M., Holt-Gosselin, B., Chang, S., Stetz, P. C., Ramirez, C. A., Hack, L. M., Korgaonkar, M. S., Wintermark, M., Gotlib, I. H., Ma, J., Williams, L. M. 2024

  Abstract

  There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.

  View details for DOI 10.1038/s41591-024-03057-9

  View details for PubMedID 38886626

  View details for PubMedCentralID 7653736

• Prevalence and characteristics of preoperative patients with depression. British journal of anaesthesia Hietamies, T. M., Smith, A. E., Lii, T. R., Muzzall, E., Flohr, J., Okada, R. L., Andriella, Z. G., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Heifets, B. D. 2024

  Abstract

  Within the perioperative period, depression-related diagnoses are associated with postoperative complications. We developed a perioperative depression screening programme to assess disease prevalence and feasibility for intervention.Adult patients in multiple surgical departments at a single academic centre were screened for depression via the electronic health record patient portal or preoperative anaesthesia clinic before surgery, using the Patient Health Questionnaire (PHQ)-2 and -8. We utilised a broad method, screening all patients, and a focused method, only screening patients with a history of depression. Logistic regression was used to identify characteristics associated with clinically significant depression (PHQ-8 ≥10). Symptomatic patients were administered a brief psychoeducational intervention and referred for mental health services.A total of 3735 patients were identified by the broad and focused screens, of whom 2940 (79%) returned PHQ-2 data and were included in analysis. The broad screen (N=1216) found 46 (4%) patients who reported symptoms of moderate or greater severity. The focused screen (N=1724) found 242 (14%) patients with symptoms of moderate or greater severity and over all higher rates of depression across the symptom severity scale. Using the total screened pool, logistic regression identified a history of depression as the strongest associated patient characteristic variable but this did not capture most cases. Finally, we found that 66% of patients who were contacted about mental health services accepted referrals or sought outside care.At least 4% of preoperative patients have clinically significant symptoms of depression, most of whom do not have a chart history of depression.

  View details for DOI 10.1016/j.bja.2024.04.017

  View details for PubMedID 38782617

• Targeting the Cognitive Biotype of Depression With a Selective Alpha 2A Receptor Agonist Using a Stratified Precision Medicine Design Hack, L., Jubeir, J., Hilton, R., Tozzi, L., Schatzberg, A., O'Hara, R., Williams, L. ELSEVIER SCIENCE INC. 2024: S165

  View details for Web of Science ID 001282811900386

• Clinical Outcomes and Biomarkers From a Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients Heifets, B., Lii, T., Smith, A., Flohr, J., Nyongesa, C., Cianfichi, L., Hack, L., Schatzberg, A. ELSEVIER SCIENCE INC. 2024: S47

  View details for Web of Science ID 001282811900110

• Opioid Use Diminishes Placebo Antidepressant Response Independently of Pain in a Ketamine Depression Trial: A Post Hoc Analysis Lii, T., Smith, A., Flohr, J., Okada, R., Nyongesa, C., Cianfichi, L., Hack, L., Schatzberg, A., Heifets, B. ELSEVIER SCIENCE INC. 2024: S184-S185

  View details for Web of Science ID 001282811900431

• Insight From Integrating Objective Data Into Psychiatric Encounters PSYCHIATRIC ANNALS Hack, L. M., Williams, L. M. 2024; 54 (4): e113-e118

  View details for DOI 10.3928/00485713-20240314-02

  View details for Web of Science ID 001209479600002

• Reduction in Trauma-Related Symptoms After Anesthetic-Induced Intra-Operative Dreaming. The American journal of psychiatry Hack, L. M., Sikka, P., Zhou, K., Kawai, M., Chow, H. S., Heifets, B. 2024: appiajp20230698

  View details for DOI 10.1176/appi.ajp.20230698

  View details for PubMedID 38476046

• Association of Neuropsychiatric Symptoms with Inflammation: Review Findings from the Workshop on Brain Immune Interactions Jha, M., Sforzini, L., Milaneschi, Y., Godin, O., Hack, L. M., Pariante, C. M., Miller, A. H., Timmie, W. P., Leboyer, M. PERGAMON-ELSEVIER SCIENCE LTD. 2024

  View details for DOI 10.1016/j.psyneuen.2023.106896

  View details for Web of Science ID 001300949100216

• Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nature mental health Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2023; 1 (11): 876-886

  Abstract

  Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. We present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (ClinicalTrials.gov, NCT03861988). Forty adult patients with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during usual anesthesia. All participants, investigators, and direct patient care staff were masked to treatment allocation. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (-5.82, 95% CI -13.3 to 1.64, p=0.13). 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias.

  View details for DOI 10.1038/s44220-023-00140-x

  View details for PubMedID 38188539

  View details for PubMedCentralID PMC10769130

• Ketamine's acute effects on negative brain states are mediated through distinct altered states of consciousness in humans. Nature communications Hack, L. M., Zhang, X., Heifets, B. D., Suppes, T., van Roessel, P. J., Yesavage, J. A., Gray, N. J., Hilton, R., Bertrand, C., Rodriguez, C. I., Deisseroth, K., Knutson, B., Williams, L. M. 2023; 14 (1): 6631

  Abstract

  Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain's affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals.

  View details for DOI 10.1038/s41467-023-42141-5

  View details for PubMedID 37857620

  View details for PubMedCentralID 5126726

• A Cognitive Biotype of Depression and Symptoms, Behavior Measures, Neural Circuits, and Differential Treatment Outcomes: A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA network open Hack, L. M., Tozzi, L., Zenteno, S., Olmsted, A. M., Hilton, R., Jubeir, J., Korgaonkar, M. S., Schatzberg, A. F., Yesavage, J. A., O'Hara, R., Williams, L. M. 2023; 6 (6): e2318411

  Abstract

  Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes.To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities.This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023.Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging.A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = -0.25; 95% CI, -0.39 to -0.11; P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d = -0.78; 95% CI, -1.28 to -0.27; P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P = .04) and cognitive impairments persisted regardless of symptom change (executive function: ηp2 = 0.241; P < .001; response inhibition: ηp2 = 0.750; P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse.Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction.ClinicalTrials.gov Identifier: NCT00693849.

  View details for DOI 10.1001/jamanetworkopen.2023.18411

  View details for PubMedID 37318808

• Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients. medRxiv : the preprint server for health sciences Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2023

  Abstract

  BACKGROUND: Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials.METHODS: In a triple-masked, randomized, placebo-controlled trial, 40 adult patients with major depressive disorder were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during anesthesia for routine surgery. The primary outcome was depression severity measured by the Montgomery-Asberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. The secondary outcome was the proportion of participants with clinical response (≥50% reduction in MADRS scores) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received.RESULTS: Mean MADRS scores did not differ between groups at screening or pre-infusion baseline. The mixed-effects model showed no evidence of effect of group assignment on post-infusion MADRS scores at 1 to 3 days post-infusion (-5.82, 95% CI -13.3 to 1.64, p=0.13). Clinical response rates were similar between groups (60% versus 50% on day 1) and comparable to previous studies of ketamine in depressed populations. Secondary and exploratory outcomes found no evidence of benefit for ketamine. 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions.CONCLUSION: A single dose of intravenous ketamine compared to placebo has no short-term effect on the severity of depression symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. While it is impractical to use surgical anesthesia for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias. ( ClinicalTrials.gov number, NCT03861988 ).

  View details for DOI 10.1101/2023.04.28.23289210

  View details for PubMedID 37205558

• A Cognitive Biotype of Depression Linking Symptoms, Behavior Measures, Neural Circuits, and Treatment Outcomes Hack, L., Tozzi, L., Zenteno, S., Olmsted, A., Hilton, R., Yesavage, J., Schatzberg, A., O'Hara, R., Williams, L. ELSEVIER SCIENCE INC. 2023: S72-S73

  View details for Web of Science ID 000993018500174

• Ketamine's Acute Effects on Negative Brain States are Mediated Through Distinct Altered States in Humans Zhang, X., Hack, L., Heifets, B., Suppes, T., Van Roessel, P., Yesavage, J., Gray, N., Hilton, R., Rodriguez, C., Deisseroth, K., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2023: S312

  View details for Web of Science ID 000993018500757

• Acute Effects of MDMA on Negative Affective Brain Circuit Function: A Randomized Controlled Mechanistic Trial Hack, L., Zhang, X., Heifets, B., Suppes, T., van Roessel, P., Yesavage, J., Gray, N., Hilton, R., Rodriguez, C., Deisseroth, K., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2023: S88

  View details for Web of Science ID 000993018500209

• Acute Effects of MDMA on Intrinsic Functional Connectomes Associated With Altered States of Consciousness and Defensiveness Zhang, X., Hack, L., Heifets, B., Suppes, T., van Roessel, P., Yesavage, J., Gray, N., Hilton, R., Rodriguez, C., Deisseroth, K., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2023: S87-S88

  View details for Web of Science ID 000993018500208

• Anesthetic-Induced Intraoperative Dream Associated With Remission of a Psychiatric Disorder: A Case Report. A&A practice Chow, H. S., Hack, L. M., Kawai, M., Heifets, B. D. 2022; 16 (8): e01613

  Abstract

  Trauma is associated with debilitating acute and posttraumatic stress disorders, which have limited treatment options. We report on a patient undergoing surgical hand repair after a recent knife attack who experienced vivid dreaming and subsequent remission of acute stress disorder. After local anesthesia with propofol sedation she recalled a dream wherein she relived the attack, sought medical care, completed surgery, and returned home with a healed hand. While intraoperative dreaming is common, this case details potential associations between anesthetic state, dreaming, intraoperative electroencephalography, and remission of a psychiatric disorder. Our experience suggests a novel intervention for stress disorders.

  View details for DOI 10.1213/XAA.0000000000001613

  View details for PubMedID 35952341

• Deconstructing Ketamine-Induced Changes in Cortisol and Dissociative and Affective States in a Controlled Mechanistic Study Hack, L. M., Zhang, X., Brawer, J., Gray, N., Heifets, B., Suppes, T., van Roessel, P., Rodriguez, C., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2022: S178-S179

  View details for Web of Science ID 000789022200436

• Acute Ketamine Modulates Cognitive Control Network Activity During Cognitive Inhibition: Evidence From a Mechanistic Trial Zhang, X., Hack, L., Brawer, J., Gray, N., Heifets, B., Suppes, T., van Roessel, P., Rodriguez, C., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2022: S225

  View details for Web of Science ID 000789022200552

• Survivors of SARS-CoV-2 Infection Show Neuropsychiatric Sequelae Measured by Surveys, Neurocognitive Testing, and Magnetic Resonance Imaging: Preliminary Results Hack, L., Brawer, J., Zhang, X., Wintermark, M., Jiang, B., Stetz, P., Yesavage, J., Grant, P., Bonilla, H., Subramanian, A., Williams, L. SPRINGERNATURE. 2021: 205-206

  View details for Web of Science ID 000725511400390

• Striato-Cortical Neuroimaging Markers in the Reward Network Distinguish Melancholic Depression and Response to Treatment: An iSPOT-D Report Hack, L. M., Zhang, X., Williams, L. M. ELSEVIER SCIENCE INC. 2021: S270

  View details for Web of Science ID 000645683800648

• Epigenetic prediction of 17β-estradiol and relationship to trauma-related outcomes in women. Comprehensive psychoneuroendocrinology Hack, L. M., Nishitani, S., Knight, A. K., Kilaru, V., Maddox, S. A., Seligowski, A. V., Jovanovic, T., Ressler, K. J., Smith, A. K., Michopoulos, V. 2021; 6: 100045

  Abstract

  17β-estradiol (E2) levels in women correlate with multiple neuropsychiatric symptoms, including those that are stress-related. Furthermore, prior work from our group has demonstrated that E2 status influences DNA methylation (DNAm) across the genome. We developed and validated a DNAm-based predictor of E2 (one of four naturally occurring estrogens) using a training set of 183 females and a test set of 79 females from the same traumatized cohort. We showed that predicted E2 levels were highly correlated with measured E2 concentrations in our testing set (r ​= ​0.75, p ​= ​1.8e-15). We further demonstrated that predicted E2 concentrations, in combination with measured values, negatively correlated with current post-traumatic stress disorder (PTSD) (β ​= ​-0.38, p ​= ​0.01) and major depressive disorder (MDD) diagnoses (β ​= ​-0.45, p ​= ​0.02), as well as a continuous measure of PTSD symptom severity (β ​= ​-2.3, p ​= ​0.007) in females. Finally, we tested our predictor in an independent data set (n ​= ​85) also comprised of recently traumatized female subjects to determine if the predictor would generalize to a different population than the one on which it was developed. We found that the correlation between predicted and actual E2 concentrations in the external validation data set was also high (r ​= ​0.48, p ​= ​3.0e-6). While further validation is warranted, a DNAm predictor of E2 concentrations will advance our understanding of hormone-epigenetic interactions. Furthermore, such a DNAm predictor may serve as an epigenetic proxy for E2 concentrations and thus provide an important biomarker to better evaluate the contribution of E2 to current and potentially future psychiatric symptoms in samples for which E2 is not measured.

  View details for DOI 10.1016/j.cpnec.2021.100045

  View details for PubMedID 35757356

  View details for PubMedCentralID PMC9216622

• Identifying response and predictive biomarkers for Transcranial magnetic stimulation outcomes: protocol and rationale for a mechanistic study of functional neuroimaging and behavioral biomarkers in veterans with Pharmacoresistant depression. BMC psychiatry Williams, L. M., Coman, J. T., Stetz, P. C., Walker, N. C., Kozel, F. A., George, M. S., Yoon, J., Hack, L. M., Madore, M. R., Lim, K. O., Philip, N. S., Holtzheimer, P. E. 2021; 21 (1): 35

  Abstract

  BACKGROUND: Although repetitive transcranial magnetic stimulation ('TMS') is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge we evaluate neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate. We evaluate whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes. This study is designed as a pragmatic, mechanistic trial partnering with the National Clinical TMS Program of the Veteran's Health Administration.METHODS: Target enrollment consists of 100 veterans with pharmacoresistant Major Depressive Disorder (MDD). All veterans will receive a clinical course of TMS and will be assessed at 'baseline' pre-TMS commencement, 'first week' after initiation of TMS (targeting five sessions) and 'post-treatment' at the completion of TMS (targeting 30 sessions). Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires. Multivariate linear mixed models will be used to assess whether neural targets change with TMS as a function of dose (Aim 1), whether extent and change of neural target relates to and predicts extent of behavioral performance (Aim 3), and whether extent of neural target change predicts improvement in symptom severity, suicidality, and quality of life (Aim 3). For all three aims, we will also assess the contribution of baseline moderators such as biological sex and age.DISCUSSION: To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD. The results of this trial will allow providers to select suitable candidates for TMS treatment and better predict treatment response by assessing circuit connectivity and cognitive-behavioral performance at baseline and during early treatment.TRIAL REGISTRATION: ClinicalTrials.gov NCT04663481 , December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020.

  View details for DOI 10.1186/s12888-020-03030-z

  View details for PubMedID 33435926

• Precision Psychiatry: Using Neuroscience Insights to Inform Personally Tailored, Measurement-Based Care edited by Williams, L. M., Hack, L. M. American Psychiatric Association. 2021
• Ventral-Hippocampal Afferents to Nucleus Accumbens Encode Both Latent Vulnerability and Stress-Induced Susceptibility Fischer, A., Holt-Gosselin, B., Fleming, S., Hack, L., Ball, T., Schatzberg, A., Williams, L. SPRINGERNATURE. 2020: 312

  View details for Web of Science ID 000596371000574

• The Effect of Selective D3 Agonism on Anhedonia Symptoms and Reward Neurocircuitry in Subjects With MDD and Prominent Anhedonia Hack, L., Keller, A. S., Warthen, K. G., Whicker, C., Williams, L. M. SPRINGERNATURE. 2020: 96–97

  View details for Web of Science ID 000596371000193

• Intrinsic reward circuit connectivity profiles underlying symptom and quality of life outcomes following antidepressant medication: a report from the iSPOT-D trial. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Fischer, A. S., Holt-Gosselin, B., Fleming, S. L., Hack, L. M., Ball, T. M., Schatzberg, A. F., Williams, L. M. 2020

  Abstract

  There is a critical need to better understand the neural basis of antidepressant medication (ADM) response with respect to both symptom alleviation and quality of life (QoL) in major depressive disorder (MDD). Reward neurocircuitry has been implicated in QoL, the neural basis of MDD, and the mechanisms of ADM response. Yet, we do not know whether change in reward neurocircuitry as a function of ADM is associated with change in symptoms and QoL. To address this gap in knowledge, we analyzed data from 128 patients with MDD who participated in the iSPOT-D trial and were assessed with functional neuroimaging pre- and post-ADM treatment (randomized to sertraline, venlafaxine-XR, or escitalopram). 58 matched healthy controls were scanned at the same time points. We quantified functional connectivity (FC) of reward neurocircuitry using nucleus accumbens (NAc) seed regions of interest, and then characterized how changes in FC relate to symptom response (primary outcome) and QoL response (secondary outcome). Symptom responders showed an increase in NAc-dorsal anterior cingulate cortex (ACC) FC relative to non-responders (p<0.001) which was associated with improvement in physical QoL (p<0.0003), and a decrease in NAc-inferior parietal lobule FC relative to controls (p<0.001). QoL response was characterized by increases in FC between NAc-ventral ACC for environmental, NAc-thalamus for physical, and NAc-paracingulate gyrus for social domains (p<0.001). Symptom responders to sertraline were distinguished by a decrease in NAc-insula FC (p<0.001) and to venlafaxine-XR by an increase in NAc-inferior temporal gyrus FC (p<0.005). Findings suggest that change in reward neurocircuitry may underlie differential ADM response profiles with respect to symptoms and QoL in depression.

  View details for DOI 10.1038/s41386-020-00905-3

  View details for PubMedID 33230268

• A precision medicine-based, 'fast-fail' approach for psychiatry. Nature medicine Williams, L. M., Hack, L. M. 2020; 26 (5): 653–54

  View details for DOI 10.1038/s41591-020-0854-z

  View details for PubMedID 32405056

• Functional Connectivity of Reward Circuitry is a Core Mechanistic Biomarker of Treatment Response and Quality of Life in Depression Holt-Gosselin, B., Fischer, A., Fleming, S., Hack, L., Ball, T., Schatzberg, A., Williams, L. M. ELSEVIER SCIENCE INC. 2020: S396–S397

  View details for Web of Science ID 000535308201213

• Mechanistic Trial Evaluating the Effect of Repetitive Transcranial Magnetic Stimulation on RDoC Constructs in Treatment-Resistant Depression Hack, L. M., Keller, A. S., Whicker, C., Williams, L. M. ELSEVIER SCIENCE INC. 2020: S412–S413

  View details for Web of Science ID 000535308201252

• Exploring Nonmotor Neuropsychiatric Manifestations of Parkinson Disease in a Comprehensive Care Setting. Journal of geriatric psychiatry and neurology Dhingra, A., Janjua, A. U., Hack, L., Waserstein, G., Palanci, J., Hermida, A. P. 2020: 891988720915525

  Abstract

  Parkinson disease (PD) is a debilitating neurological condition that includes both motor symptoms and nonmotor symptoms (NMS). Psychiatric complaints comprise NMS and are collectively referred to as neuropsychiatric manifestations. Common findings include atypical depressive symptoms, anxiety, psychosis, impulse control disorder, deterioration of cognition, and sleep disturbances. Quality of life (QoL) of patients suffering from NMS is greatly impacted and many times can be more debilitating than motor symptoms of PD. We expand on knowledge gained from treatment models within a comprehensive care model that incorporates multidisciplinary specialists working alongside psychiatrists to treat PD. Insight into background, clinical presentations, and treatment options for patients suffering from neuropsychiatric manifestations of PD are discussed. Identifying symptoms early can help improve QoL, provide early symptom relief, and can assist tailoring treatment plans that limit neuropsychiatric manifestations.

  View details for DOI 10.1177/0891988720915525

  View details for PubMedID 32242493

• Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium. Molecular psychiatry Polimanti, R., Walters, R. K., Johnson, E. C., McClintick, J. N., Adkins, A. E., Adkins, D. E., Bacanu, S., Bierut, L. J., Bigdeli, T. B., Brown, S., Bucholz, K. K., Copeland, W. E., Costello, E. J., Degenhardt, L., Farrer, L. A., Foroud, T. M., Fox, L., Goate, A. M., Grucza, R., Hack, L. M., Hancock, D. B., Hartz, S. M., Heath, A. C., Hewitt, J. K., Hopfer, C. J., Johnson, E. O., Kendler, K. S., Kranzler, H. R., Krauter, K., Lai, D., Madden, P. A., Martin, N. G., Maes, H. H., Nelson, E. C., Peterson, R. E., Porjesz, B., Riley, B. P., Saccone, N., Stallings, M., Wall, T. L., Webb, B. T., Wetherill, L., Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Edenberg, H. J., Agrawal, A., Gelernter, J. 2020

  Abstract

  To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z=-5.39, p=7.2*10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N>360,000) found association of this variant with propensity to use dietary supplements (p=1.68*10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR+AFR z=4.69, p=10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z=5.55, p=2.9*10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p=4.88*10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n=466,571) was positively associated with OD (OD vs. unexposed controls, p=8.1*10-5; OD cases vs. exposed controls, p=0.054) and OE (exposed vs. unexposed controls, p=3.6*10-5). A PRS based on a GWAS of neuroticism (n=390,278) was positively associated with OD (OD vs. unexposed controls, p=3.2*10-5; OD vs. exposed controls, p=0.002) but not with OE (p=0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

  View details for DOI 10.1038/s41380-020-0677-9

  View details for PubMedID 32099098

• Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies. Addiction biology Munn-Chernoff, M. A., Johnson, E. C., Chou, Y., Coleman, J. R., Thornton, L. M., Walters, R. K., Yilmaz, Z., Baker, J. H., Hubel, C., Gordon, S., Medland, S. E., Watson, H. J., Gaspar, H. A., Bryois, J., Hinney, A., Leppa, V. M., Mattheisen, M., Ripke, S., Yao, S., Giusti-Rodriguez, P., Hanscombe, K. B., Adan, R. A., Alfredsson, L., Ando, T., Andreassen, O. A., Berrettini, W. H., Boehm, I., Boni, C., Boraska Perica, V., Buehren, K., Burghardt, R., Cassina, M., Cichon, S., Clementi, M., Cone, R. D., Courtet, P., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S., de Zwaan, M., Dedoussis, G., Degortes, D., DeSocio, J. E., Dick, D. M., Dikeos, D., Dina, C., Dmitrzak-Weglarz, M., Docampo, E., Duncan, L. E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Farmer, A., Favaro, A., Fernandez-Aranda, F., Fichter, M. M., Fischer, K., Focker, M., Foretova, L., Forstner, A. J., Forzan, M., Franklin, C. S., Gallinger, S., Giegling, I., Giuranna, J., Gonidakis, F., Gorwood, P., Gratacos Mayora, M., Guillaume, S., Guo, Y., Hakonarson, H., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S. G., Herms, S., Herpertz-Dahlmann, B., Herzog, W., Huckins, L. M., Hudson, J. I., Imgart, H., Inoko, H., Janout, V., Jimenez-Murcia, S., Julia, A., Kalsi, G., Kaminska, D., Karhunen, L., Karwautz, A., Kas, M. J., Kennedy, J. L., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y., Klump, K. L., Knudsen, G. P., La Via, M. C., Le Hellard, S., Levitan, R. D., Li, D., Lilenfeld, L., Lin, B. D., Lissowska, J., Luykx, J., Magistretti, P. J., Maj, M., Mannik, K., Marsal, S., Marshall, C. R., Mattingsdal, M., McDevitt, S., McGuffin, P., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, K., Monteleone, A. M., Monteleone, P., Nacmias, B., Navratilova, M., Ntalla, I., O'Toole, J. K., Ophoff, R. A., Padyukov, L., Palotie, A., Pantel, J., Papezova, H., Pinto, D., Rabionet, R., Raevuori, A., Ramoz, N., Reichborn-Kjennerud, T., Ricca, V., Ripatti, S., Ritschel, F., Roberts, M., Rotondo, A., Rujescu, D., Rybakowski, F., Santonastaso, P., Scherag, A., Scherer, S. W., Schmidt, U., Schork, N. J., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M. C., Slopien, A., Sorbi, S., Swiatkowska, B., Szatkiewicz, J. P., Tachmazidou, I., Tenconi, E., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tyszkiewicz-Nwafor, M., Tziouvas, K., van Elburg, A. A., van Furth, E. F., Wagner, G., Walton, E., Widen, E., Zeggini, E., Zerwas, S., Zipfel, S., Bergen, A. W., Boden, J. M., Brandt, H., Crawford, S., Halmi, K. A., Horwood, L. J., Johnson, C., Kaplan, A. S., Kaye, W. H., Mitchell, J., Olsen, C. M., Pearson, J. F., Pedersen, N. L., Strober, M., Werge, T., Whiteman, D. C., Woodside, D. B., Grove, J., Henders, A. K., Larsen, J. T., Parker, R., Petersen, L. V., Jordan, J., Kennedy, M. A., Birgegard, A., Lichtenstein, P., Norring, C., Landen, M., Mortensen, P. B., Polimanti, R., McClintick, J. N., Adkins, A. E., Aliev, F., Bacanu, S., Batzler, A., Bertelsen, S., Biernacka, J. M., Bigdeli, T. B., Chen, L., Clarke, T., Degenhardt, F., Docherty, A. R., Edwards, A. C., Foo, J. C., Fox, L., Frank, J., Hack, L. M., Hartmann, A. M., Hartz, S. M., Heilmann-Heimbach, S., Hodgkinson, C., Hoffmann, P., Hottenga, J., Konte, B., Lahti, J., Lahti-Pulkkinen, M., Lai, D., Ligthart, L., Loukola, A., Maher, B. S., Mbarek, H., McIntosh, A. M., McQueen, M. B., Meyers, J. L., Milaneschi, Y., Palviainen, T., Peterson, R. E., Ryu, E., Saccone, N. L., Salvatore, J. E., Sanchez-Roige, S., Schwandt, M., Sherva, R., Streit, F., Strohmaier, J., Thomas, N., Wang, J., Webb, B. T., Wedow, R., Wetherill, L., Wills, A. G., Zhou, H., Boardman, J. D., Chen, D., Choi, D., Copeland, W. E., Culverhouse, R. C., Dahmen, N., Degenhardt, L., Domingue, B. W., Frye, M. A., Gabel, W., Hayward, C., Ising, M., Keyes, M., Kiefer, F., Koller, G., Kramer, J., Kuperman, S., Lucae, S., Lynskey, M. T., Maier, W., Mann, K., Mannisto, S., Muller-Myhsok, B., Murray, A. D., Nurnberger, J. I., Preuss, U., Raikkonen, K., Reynolds, M. D., Ridinger, M., Scherbaum, N., Schuckit, M. A., Soyka, M., Treutlein, J., Witt, S. H., Wodarz, N., Zill, P., Adkins, D. E., Boomsma, D. I., Bierut, L. J., Brown, S. A., Bucholz, K. K., Costello, E. J., de Wit, H., Diazgranados, N., Eriksson, J. G., Farrer, L. A., Foroud, T. M., Gillespie, N. A., Goate, A. M., Goldman, D., Grucza, R. A., Hancock, D. B., Harris, K. M., Hesselbrock, V., Hewitt, J. K., Hopfer, C. J., Iacono, W. G., Johnson, E. O., Karpyak, V. M., Kendler, K. S., Kranzler, H. R., Krauter, K., Lind, P. A., McGue, M., MacKillop, J., Madden, P. A., Maes, H. H., Magnusson, P. K., Nelson, E. C., Nothen, M. M., Palmer, A. A., Penninx, B. W., Porjesz, B., Rice, J. P., Rietschel, M., Riley, B. P., Rose, R. J., Shen, P., Silberg, J., Stallings, M. C., Tarter, R. E., Vanyukov, M. M., Vrieze, S., Wall, T. L., Whitfield, J. B., Zhao, H., Neale, B. M., Wade, T. D., Heath, A. C., Montgomery, G. W., Martin, N. G., Sullivan, P. F., Kaprio, J., Breen, G., Gelernter, J., Edenberg, H. J., Bulik, C. M., Agrawal, A. 2020: e12880

  Abstract

  Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

  View details for DOI 10.1111/adb.12880

  View details for PubMedID 32064741

• A large-scale genome-wide association study meta-analysis of cannabis use disorder. The lancet. Psychiatry Johnson, E. C., Demontis, D. n., Thorgeirsson, T. E., Walters, R. K., Polimanti, R. n., Hatoum, A. S., Sanchez-Roige, S. n., Paul, S. E., Wendt, F. R., Clarke, T. K., Lai, D. n., Reginsson, G. W., Zhou, H. n., He, J. n., Baranger, D. A., Gudbjartsson, D. F., Wedow, R. n., Adkins, D. E., Adkins, A. E., Alexander, J. n., Bacanu, S. A., Bigdeli, T. B., Boden, J. n., Brown, S. A., Bucholz, K. K., Bybjerg-Grauholm, J. n., Corley, R. P., Degenhardt, L. n., Dick, D. M., Domingue, B. W., Fox, L. n., Goate, A. M., Gordon, S. D., Hack, L. M., Hancock, D. B., Hartz, S. M., Hickie, I. B., Hougaard, D. M., Krauter, K. n., Lind, P. A., McClintick, J. N., McQueen, M. B., Meyers, J. L., Montgomery, G. W., Mors, O. n., Mortensen, P. B., Nordentoft, M. n., Pearson, J. F., Peterson, R. E., Reynolds, M. D., Rice, J. P., Runarsdottir, V. n., Saccone, N. L., Sherva, R. n., Silberg, J. L., Tarter, R. E., Tyrfingsson, T. n., Wall, T. L., Webb, B. T., Werge, T. n., Wetherill, L. n., Wright, M. J., Zellers, S. n., Adams, M. J., Bierut, L. J., Boardman, J. D., Copeland, W. E., Farrer, L. A., Foroud, T. M., Gillespie, N. A., Grucza, R. A., Harris, K. M., Heath, A. C., Hesselbrock, V. n., Hewitt, J. K., Hopfer, C. J., Horwood, J. n., Iacono, W. G., Johnson, E. O., Kendler, K. S., Kennedy, M. A., Kranzler, H. R., Madden, P. A., Maes, H. H., Maher, B. S., Martin, N. G., McGue, M. n., McIntosh, A. M., Medland, S. E., Nelson, E. C., Porjesz, B. n., Riley, B. P., Stallings, M. C., Vanyukov, M. M., Vrieze, S. n., Davis, L. K., Bogdan, R. n., Gelernter, J. n., Edenberg, H. J., Stefansson, K. n., Børglum, A. D., Agrawal, A. n. 2020

  Abstract

  Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

  View details for DOI 10.1016/S2215-0366(20)30339-4

  View details for PubMedID 33096046

• Unpacking Genetic Risk Pathways for College Student Alcohol Consumption: The Mediating Role of Impulsivity. Alcoholism, clinical and experimental research Ksinan, A. J., Su, J., Aliev, F., Dick, D. M. 2019

  Abstract

  The period of college represents a particularly risky developmental stage with regard to alcohol use, as college students engage in more risky drinking behaviors than their noncollege peers, and such problematic alcohol use is associated with far-reaching negative consequences. Existing findings from genome-wide association studies (GWAS) indicate that alcohol consumption has a complex polygenic etiology. Currently, there is a lack of studies examining genetic risk for alcohol consumption using polygenic risk scores (PRS) in college samples. In this study, we examined whether alcohol-specific and risky behavior-related PRS were longitudinally associated with alcohol consumption among college students and whether this effect might be partially mediated by impulsivity domains.The sample included n = 2,385 European ancestry (EA) and n = 1,153 African ancestry (AA) college students assessed over the course of 4 years. To indicate genetic risk, 2 PRS were created based on recent large-scale GWAS: alcohol consumption (Liu et al., 2019) -drinks per week (DPW)-PRS and risky behaviors (Linnér et al., 2019) -RISK-PRS. The main outcome was alcohol consumption, measured across 4 waves of follow-up data. The UPPS-P impulsivity subscales were examined as mediators of the genetic effect on alcohol consumption.The results from structural equation modeling showed that among EA students, both DPW-PRS and RISK-PRS had significant positive effects on alcohol consumption above and beyond UPPS dimensions and control variables. RISK-PRS explained larger portion of variance in alcohol consumption than DPW-PRS. RISK-PRS showed a significant indirect effect on alcohol consumption through sensation seeking and lack of perseverance; no significant indirect effect of DPW-PRS was found. No significant association of either PRS or alcohol consumption was found for AA participants.The current results found that PRS related to more broadly defined risky behaviors predicted alcohol consumption across college years and that this association was partially mediated via dimensions of impulsivity.

  View details for DOI 10.1111/acer.14157

  View details for PubMedID 31373688

• Genes, Roommates, and Residence Halls: A Multidimensional Study of the Role of Peer Drinking on College Students' Alcohol Use. Alcoholism, clinical and experimental research Smith, R. L., Salvatore, J. E., Aliev, F., Neale, Z., Barr, P., Dick, D. M. 2019; 43 (6): 1254-1262

  Abstract

  Peer drinking is one of the most robust predictors of college students' alcohol use and can moderate students' genetic risk for alcohol use. Peer effect research generally suffers from 2 problems: selection into peer groups and relying more on perceptions of peer alcohol use than peers' self-report. The goal of the present study was to overcome those limitations by capitalizing on a genetically informed sample of randomly assigned college roommates to examine multiple dimensions of peer influence and the interplay between peer effects and genetic predisposition on alcohol use, in the form of polygenic scores.We used a subsample (n = 755) of participants from a university-wide, longitudinal study at a large, diverse, urban university. Participants reported their own alcohol use during fall and spring and their perceptions of college peers' alcohol use in spring. We matched individuals into their rooms and residence halls to create a composite score of peer-reported alcohol use for each of those levels. We examined multiple dimensions of peer influence and whether peer influence moderated genetic predisposition to predict college students' alcohol use using multilevel models to account for clustering at the room and residence hall level.We found that polygenic scores (β = 0.12), perceptions of peer drinking (β = 0.37), and roommates' self-reported drinking (β = 0.10) predicted alcohol use (all ps < 0.001), while average alcohol use across residence hall did not (β = -0.01, p = 0.86). We found no evidence for interactions between peer influence and genome-wide polygenic scores for alcohol use.Our findings underscore the importance of genetic predisposition on individual alcohol use and support the potentially causal nature of the association between peer influence and alcohol use.

  View details for DOI 10.1111/acer.14037

  View details for PubMedID 31034622

  View details for PubMedCentralID PMC6561118

• Moving pharmacoepigenetics tools for depression toward clinical use. Journal of affective disorders Hack, L. M., Fries, G. R., Eyre, H. A., Bousman, C. A., Singh, A. B., Quevedo, J. n., John, V. P., Baune, B. T., Dunlop, B. W. 2019; 249: 336–46

  Abstract

  Major depressive disorder (MDD) is a leading cause of disability worldwide, and over half of patients do not achieve symptom remission following an initial antidepressant course. Despite evidence implicating a strong genetic basis for the pathophysiology of MDD, there are no adequately validated biomarkers of treatment response routinely used in clinical practice. Pharmacoepigenetics is an emerging field that has the potential to combine both genetic and environmental information into treatment selection and further the goal of precision psychiatry. However, this field is in its infancy compared to the more established pharmacogenetics approaches.We prepared a narrative review using literature searches of studies in English pertaining to pharmacoepigenetics and treatment of depressive disorders conducted in PubMed, Google Scholar, PsychINFO, and Ovid Medicine from inception through January 2019. We reviewed studies of DNA methylation and histone modifications in both humans and animal models of depression.Emerging evidence from human and animal work suggests a key role for epigenetic marks, including DNA methylation and histone modifications, in the prediction of antidepressant response. The challenges of heterogeneity of patient characteristics and loci studied as well as lack of replication that have impacted the field of pharmacogenetics also pose challenges to the development of pharmacoepigenetic tools. Additionally, given the tissue specific nature of epigenetic marks as well as their susceptibility to change in response to environmental factors and aging, pharmacoepigenetic tools face additional challenges to their development.This is a narrative and not systematic review of the literature on the pharmacoepigenetics of antidepressant response. We highlight key studies pertaining to pharmacoepigenetics and treatment of depressive disorders in humans and depressive-like behaviors in animal models, regardless of sample size or methodology. While we discuss DNA methylation and histone modifications, we do not cover microRNAs, which have been reviewed elsewhere recently.Utilization of genome-wide approaches and reproducible epigenetic assays, careful selection of the tissue assessed, and integration of genetic and clinical information into pharmacoepigenetic tools will improve the likelihood of developing clinically useful tests.

  View details for PubMedID 30802699

• Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders NATURE NEUROSCIENCE Walters, R. K., Polimanti, R., Johnson, E. C., McClintick, J. N., Adams, M. J., Adkins, A. E., Aliev, F., Bacanu, S., Batzler, A., Bertelsen, S., Biernacka, J. M., Bigdeli, T. B., Chen, L., Clarke, T., Chou, Y., Degenhardt, F., Docherty, A. R., Edwards, A. C., Fontanillas, P., Foo, J. C., Fox, L., Frank, J., Giegling, I., Gordon, S., Hack, L. M., Hartmann, A. M., Hartz, S. M., Heilmann-Heimbach, S., Herms, S., Hodgkinson, C., Hoffmann, P., Hottenga, J., Kennedy, M. A., Alanne-Kinnunen, M., Konte, B., Lahti, J., Lahti-Pulkkinen, M., Lai, D., Ligthart, L., Loukola, A., Maher, B. S., Mbarek, H., McIntosh, A. M., McQueen, M. B., Meyers, J. L., Milaneschi, Y., Palviainen, T., Pearson, J. F., Peterson, R. E., Ripatti, S., Ryu, E., Saccone, N. L., Salvatore, J. E., Sanchez-Roige, S., Schwandt, M., Sherva, R., Streit, F., Strohmaier, J., Thomas, N., Wang, J., Webb, B. T., Wedow, R., Wetherill, L., Wills, A. G., Boardman, J. D., Chen, D., Choi, D., Copeland, W. E., Culverhouse, R. C., Dahmen, N., Degenhardt, L., Domingue, B. W., Elson, S. L., Frye, M. A., Gaebel, W., Hayward, C., Ising, M., Keyes, M., Kiefer, F., Kramer, J., Kuperman, S., Lucae, S., Lynskey, M. T., Maier, W., Mann, K., Mannisto, S., Muller-Myhsok, B., Murray, A. D., Nurnberger, J. I., Palotie, A., Preuss, U., Raikkonen, K., Reynolds, M. D., Ridinger, M., Scherbaum, N., Schuckit, M. A., Soyka, M., Treutlein, J., Witt, S., Wodarz, N., Zill, P., Adkins, D. E., Boden, J. M., Boomsma, D. I., Bierut, L. J., Brown, S. A., Bucholz, K. K., Cichon, S., Costello, E., De Wit, H., Diazgranados, N., Dick, D. M., Eriksson, J. G., Farrer, L. A., Foroud, T. M., Gillespie, N. A., Goate, A. M., Goldman, D., Grucza, R. A., Hancock, D. B., Harris, K., Heath, A. C., Hesselbrock, V., Hewitt, J. K., Hopfer, C. J., Horwood, J., Iacono, W., Johnson, E. O., Kaprio, J. A., Karpyak, V. M., Kendler, K. S., Kranzler, H. R., Krauter, K., Lichtenstein, P., Lind, P. A., McGue, M., MacKillop, J., Madden, P. F., Maes, H. H., Magnusson, P., Martin, N. G., Medland, S. E., Montgomery, G. W., Nelson, E. C., Noethen, M. M., Palmer, A. A., Pedersen, N. L., Penninx, B. H., Porjesz, B., Rice, J. P., Rietschel, M., Riley, B. P., Rose, R., Rujescu, D., Shen, P., Silberg, J., Stallings, M. C., Tarter, R. E., Vanyukov, M. M., Vrieze, S., Wall, T. L., Whitfield, J. B., Zhao, H., Neale, B. M., Gelernter, J., Edenberg, H. J., Agrawal, A., 23Andme Res Team 2018; 21 (12): 1656-+

  View details for DOI 10.1038/s41593-018-0275-1

  View details for Web of Science ID 000451324700005

• Data-Driven Subtypes of Depression in a Treatment Resistant Cohort Hack, L., Janjua, A., Dover, S., Posse, P. NATURE PUBLISHING GROUP. 2018: S140

  View details for Web of Science ID 000509546600272

• Polyepigenetic Prediction of PTSD Physiology Based on Estrogen Status Seligowski, A., Maddox, S., Jovanovic, T., Michopolous, V., Hack, L., Lori, A., Ressler, K., Smith, A. ELSEVIER SCIENCE INC. 2018: S141

  View details for DOI 10.1016/j.biopsych.2018.02.369

  View details for Web of Science ID 000432466300347

• DNA Methylation Across the Genome Associates With Serum Estrogen Levels and PTSD Smith, A., Michopoulos, V., Maddox, S., Hack, L., Jovanovic, T., Ressler, K. J. ELSEVIER SCIENCE INC. 2018: S86–S87

  View details for DOI 10.1016/j.biopsych.2018.02.234

  View details for Web of Science ID 000432466300216

• Practical outpatient pharmacotherapy for alcohol use disorder. Drugs in context Kim, Y., Hack, L. M., Ahn, E. S., Kim, J. 2018; 7: 212308

  Abstract

  Alcohol use disorder (AUD) is commonly encountered in clinical practice. A combination of psychosocial intervention and pharmacotherapy is the cornerstone of AUD treatment. Despite their efficacy, safety and cost-effectiveness, clinicians are reluctant to prescribe medications to treat individuals with AUD. Given the high rate of relapse with psychosocial intervention alone, increasing patient access to this underutilized treatment has the potential to improve clinical outcome in this difficult-to-treat population. Herein, we provide practical pharmacotherapy strategies to improve treatment outcome for AUD. We review the efficacy and side effects of both on- and off-label agents with a particular focus on clinical applicability. Recommendations are supported by findings from randomized controlled trials (RCT) and meta-analyses selected to be representative, where possible, of current treatment guidelines. The goal of this paper is to help readers use pharmacotherapy with greater confidence when treating patients with AUD.

  View details for DOI 10.7573/dic.212308

  View details for PubMedID 29445407

  View details for PubMedCentralID PMC5804871

• Suicide Prediction Using Machine Learning Techniques in Screening and Clinician-Derived Data Hack, L., Jovanovic, T., Carter, S., Ressler, K., Smith, A. ELSEVIER SCIENCE INC. 2017: S361

  View details for DOI 10.1016/j.biopsych.2017.02.619

  View details for Web of Science ID 000400348700891

• Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. Alcoholism, clinical and experimental research Adkins, A. E., Hack, L. M., Bigdeli, T. B., Williamson, V. S., McMichael, G. O., Mamdani, M., Edwards, A. C., Aliev, F., Chan, R. F., Bhandari, P., Raabe, R. C., Alaimo, J. T., Blackwell, G. G., Moscati, A., Poland, R. S., Rood, B., Patterson, D. G., Walsh, D., Whitfield, J. B., Zhu, G., Montgomery, G. W., Henders, A. K., Martin, N. G., Heath, A. C., Madden, P. A., Frank, J., Ridinger, M., Wodarz, N., Soyka, M., Zill, P., Ising, M., Nöthen, M. M., Kiefer, F., Rietschel, M., Gelernter, J., Sherva, R., Koesterer, R., Almasy, L., Zhao, H., Kranzler, H. R., Farrer, L. A., Maher, B. S., Prescott, C. A., Dick, D. M., Bacanu, S. A., Mathies, L. D., Davies, A. G., Vladimirov, V. I., Grotewiel, M., Bowers, M. S., Bettinger, J. C., Webb, B. T., Miles, M. F., Kendler, K. S., Riley, B. P. 2017; 41 (5): 911-928

  Abstract

  Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified.We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue.We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc).We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.

  View details for DOI 10.1111/acer.13362

  View details for PubMedID 28226201

  View details for PubMedCentralID PMC5404949

• Epigenetic mechanisms involved in the effects of stress exposure: focus on 5-hydroxymethylcytosine. Environmental epigenetics Hack, L. M., Dick, A. L., Provençal, N. 2016; 2 (3): dvw016

  Abstract

  5-hydroxymethylcytosine (5hmC) is a recently re-discovered transient intermediate in the active demethylation pathway that also appears to play an independent role in modulating gene function. Epigenetic marks, particularly 5-methylcytosine, have been widely studied in relation to stress-related disorders given the long-lasting effect that stress has on these marks. 5hmC is a good candidate for involvement in the etiology of these disorders given its elevated concentration in mammalian neurons, its dynamic regulation during development of the central nervous system, and its high variability among individuals. Although we are unaware of any studies published to date examining 5 hmC profiles in human subjects who have developed a psychiatric disorder after a life stressor, there is emerging evidence from the animal literature that 5hmC profiles are altered in the context of fear-conditioning paradigms and stress exposure, suggesting a possible role for 5hmC in the biological underpinnings of stress-related disorders. In this review, the authors examine the available approaches for profiling 5hmC and describe their advantages and disadvantages as well as discuss the studies published thus far investigating 5hmC in the context of fear-related learning and stress exposure in animals. The authors also highlight the global versus locus-specific regulation of 5hmC in these studies. Finally, the limitations of the current studies and their implications are discussed.

  View details for DOI 10.1093/eep/dvw016

  View details for PubMedID 29492296

  View details for PubMedCentralID PMC5804530

• Exposure to Glucocorticoids During Hippocampal Neurogenesis: Effects on DNA Hydroxymethylation Hack, L. M., Provencal, N., Wiechmann, T., Koedel, M., Rex-Haffner, M., Anacker, C., Binder, E. ELSEVIER SCIENCE INC. 2016: 94S

  View details for Web of Science ID 000432440801069

• Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence. PloS one Mamdani, M., Williamson, V., McMichael, G. O., Blevins, T., Aliev, F., Adkins, A., Hack, L., Bigdeli, T., van der Vaart, A. D., Web, B. T., Bacanu, S. A., Kalsi, G., Kendler, K. S., Miles, M. F., Dick, D., Riley, B. P., Dumur, C., Vladimirov, V. I. 2015; 10 (9): e0137671

  Abstract

  Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

  View details for DOI 10.1371/journal.pone.0137671

  View details for PubMedID 26381263

  View details for PubMedCentralID PMC4575063

• GENOMEWIDE ASSOCIATION STUDY OF ALCOHOL QUANTITATIVE TRAITS IN AN IRISH SAMPLE SUPPORTS THE USE OF PHENOTYPES BEYOND ALCOHOL DEPENDENCE DIAGNOSIS Adkins, A. E., Hack, L. M., Bigdeli, T. B., Bettinger, J. C., Davies, A. G., Grotewiel, M. S., Prescott, C. A., Dick, D. M., Webb, B. T., Miles, M. S., Kendler, K. S., Riley, B. P. WILEY-BLACKWELL. 2014: 309A

  View details for Web of Science ID 000337523701435

• GENOMEWIDE ASSOCIATION STUDY OF ALCOHOL DEPENDENCE IN AN IRISH SAMPLE IDENTIFIES RISK LOCI SUPPORTED BY MODEL ORGANISM STUDIES AND CONVERGENT EVIDENCE Riley, B. P., Adkins, A. E., Hack, L. M., Bigdeli, T. B., Bettinger, J. C., Davies, A. G., Grotewiel, M. S., Prescott, C. A., Dick, D. M., Webb, B. T., Miles, M. F., Kendler, K. S. WILEY-BLACKWELL. 2014: 220A

  View details for Web of Science ID 000337523701080

• Summaries from the XIX World Congress of Psychiatric Genetics, Washington, DC, September 10-14, 2011. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Dai, N., Foldager, L., Gallego, J. A., Hack, L. M., Ji, Y., Lett, T. A., Liu, B. C., Loken, E. K., Mandelli, L., Mehta, D., Power, R. A., Sprooten, E., Stephens, S. H., Paska, A. V., Yan, J., Zai, C. C., Zai, G., Zhang-James, Y., O'Shea, A., Delisi, L. E. 2012; 159B (1): 128-9

  View details for DOI 10.1002/ajmg.b.32017

  View details for PubMedID 22180335

  View details for PubMedCentralID PMC4416401

• The Effects of leptin on thermosensitive neurons in the anterior hypothalamus of the rat Askin, C. A., Hack, L. M., Griffin, J. D. FEDERATION AMER SOC EXP BIOL. 2011

  View details for Web of Science ID 000310708400772

• Limited associations of dopamine system genes with alcohol dependence and related traits in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Alcoholism, clinical and experimental research Hack, L. M., Kalsi, G., Aliev, F., Kuo, P. H., Prescott, C. A., Patterson, D. G., Walsh, D., Dick, D. M., Riley, B. P., Kendler, K. S. 2011; 35 (2): 376-85

  Abstract

  Over 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing.We conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols.Of the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score.Our study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range of alcohol-related traits and measures of behavioral disinhibition. While we did conduct gene-based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false-positive findings remain possible, so our results must be interpreted with caution.

  View details for DOI 10.1111/j.1530-0277.2010.01353.x

  View details for PubMedID 21083670

  View details for PubMedCentralID PMC3443636

• Effects of leptin on the firing rates of thermoregulatory neurons in the anterior hypothalamus Hack, L. M., Griffin, J. D. FEDERATION AMER SOC EXP BIOL. 2006: A1247

  View details for Web of Science ID 000236326203449