Publications by authors named "Charles B Nemeroff"

349 Publications

Psychedelics and Psychedelic-Assisted Psychotherapy.

Focus (Am Psychiatr Publ) 2021 Jan 26;19(1):95-115. Epub 2020 Feb 26.

Department of Psychiatry, New York University School of Medicine, New York (Reiff); Department of Psychiatry and Human Behavior, Emory University School of Medicine, Atlanta (Richman, McDonald); Department of Psychiatry, Dell Medical School and the Institute for Early Life Adversity Research, University of Texas at Austin (Nemeroff); Department of Psychiatry and Human Behavior, Butler Hospital, Brown University, Providence, R.I. (Carpenter); Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis (Widge); Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif., and Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif. (Rodriguez); Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison (Kalin).

(Reprinted with permission from 2020; 177:391-410).
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http://dx.doi.org/10.1176/appi.focus.19104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412151PMC
January 2021

Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development.

Neuropsychopharmacology 2021 09 29;46(10):1811-1820. Epub 2021 Jun 29.

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.

Biomarkers that predict symptom trajectories after trauma can facilitate early detection or intervention for posttraumatic stress disorder (PTSD) and may also advance our understanding of its biology. Here, we aimed to identify trajectory-based biomarkers using blood transcriptomes collected in the immediate aftermath of trauma exposure. Participants were recruited from an Emergency Department in the immediate aftermath of trauma exposure and assessed for PTSD symptoms at baseline, 1, 3, 6, and 12 months. Three empirical symptom trajectories (chronic-PTSD, remitting, and resilient) were identified in 377 individuals based on longitudinal symptoms across four data points (1, 3, 6, and 12 months), using latent growth mixture modeling. Blood transcriptomes were examined for association with longitudinal symptom trajectories, followed by expression quantitative trait locus analysis. GRIN3B and AMOTL1 blood mRNA levels were associated with chronic vs. resilient post-trauma symptom trajectories at a transcriptome-wide significant level (N = 153, FDR-corrected p value = 0.0063 and 0.0253, respectively). We identified four genetic variants that regulate mRNA blood expression levels of GRIN3B. Among these, GRIN3B rs10401454 was associated with PTSD in an independent dataset (N = 3521, p = 0.04). Examination of the BrainCloud and GTEx databases revealed that rs10401454 was associated with brain mRNA expression levels of GRIN3B. While further replication and validation studies are needed, our data suggest that GRIN3B, a glutamate ionotropic receptor NMDA type subunit-3B, may be involved in the manifestation of PTSD. In addition, the blood mRNA level of GRIN3B may be a promising early biomarker for the PTSD manifestation and development.
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http://dx.doi.org/10.1038/s41386-021-01073-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357796PMC
September 2021

Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Department of Psychiatry, Dell School of Medicine, Univerity of Texas, Austin, TX, USA.

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5-12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.
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http://dx.doi.org/10.1038/s41380-021-01084-3DOI Listing
May 2021

Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Department of Psychiatry, Dell School of Medicine, Univerity of Texas, Austin, TX, USA.

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5-12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.
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http://dx.doi.org/10.1038/s41380-021-01084-3DOI Listing
May 2021

The Trifecta of Misery and Disease Vulnerability: Poverty, Childhood Maltreatment, and Inflammation.

Am J Psychiatry 2021 04;178(4):282-284

Institute of Early Life Adversity Research, Department of Psychiatry and Behavioral Sciences, University of Texas at Austin, Dell Medical School, Austin.

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http://dx.doi.org/10.1176/appi.ajp.2020.21010087DOI Listing
April 2021

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.

Am J Psychiatry 2021 05 17;178(5):383-399. Epub 2021 Mar 17.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto (McIntyre, Rosenblat, Y. Lee, Lui, Mansur); Department of Psychiatry, University of Toronto, Toronto (McIntyre, Rosenblat, Mansur); Department of Pharmacology, University of Toronto, Toronto (McIntyre); Brain and Cognition Discovery Foundation, Toronto (McIntyre, Subramaniapillai); Canadian Rapid Treatment Center of Excellence, Mississauga, Ontario (Rosenblat, Kratiuk); Department of Psychiatry and Behavioral Sciences, Austin Dell Medical School, University of Texas, Austin (Nemeroff); Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Sanacora); Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, and Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York (Murrough); Deakin University, Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia (Berk, Dodd); Orygen, National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Melbourne, Australia (Berk); Department of Psychiatry, Queen's University School of Medicine, and Centre for Neuroscience Studies, Queen's University, Kingston, Ontario (Brietzke); Centre for Youth Mental Health and Department of Psychiatry, University of Melbourne, Melbourne, Australia (Dodd); Université de Paris, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, and GHU Paris Psychiatrie et Neurosciences, CMME, Hôpital Sainte-Anne, Paris (Gorwood); Department of Psychological Medicine, Yong Loo Lin School of Medicine, and Institute of Health Innovation and Technology, National University of Singapore, Singapore (Ho); Department of Psychiatry, NYU School of Medicine, and Clinical Research Division, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York (Iosifescu); Department of Psychiatry, Universidad de Antioquia, Medellin, Colombia (Lopez Jaramillo); Center for Brain Research, Medical University of Vienna, Vienna (Kasper); Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland (Kratiuk); Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Paik Institute for Clinical Research, and Department of Health Science and Technology, Graduate School, Inje University, Busan, Republic of Korea (J.G. Lee); Institute of Medical Science, University of Toronto, Toronto (Y. Lee); Clinical Trials Network and Institute, Massachusetts General Hospital, Boston (Papakostas); Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, and Corporal Michael J. Crescenz VA Medical Center, Philadelphia (Thase); Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona (Vieta); Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London and South London, and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, Kent (Young); Experimental Therapeutics and Pathophysiology Branch and Section on the Neurobiology and Treatment of Mood Disorders, Division of Intramural Research Program, NIMH, Bethesda, Md. (Zarate); Department of Psychiatry and Neuroscience, University of California, Riverside, and University of California, San Diego (Stahl).

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
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http://dx.doi.org/10.1176/appi.ajp.2020.20081251DOI Listing
May 2021

Efficacy of Vortioxetine Monotherapy for Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial.

J Clin Psychopharmacol 2021 Mar-Apr 01;41(2):172-179

Department of Psychiatry and Behavioral Sciences, Institute for Early Life Adversity Research, University of Texas at Austin Dell Medical School, Austin, TX.

Purpose/background: There are few efficacious pharmacological treatments for posttraumatic stress disorder (PTSD) and many patients fail to benefit from existing treatments. Vortioxetine, a recently developed antidepressant, acts as a serotonin modulator through inhibition of the serotonin transporter and actions at multiple types of serotonin receptors. Its unique pharmacodynamic profile suggests it may have efficacy for the treatment of PTSD.

Methods/procedures: We conducted a 12-week placebo-controlled, randomized clinical trial of vortioxetine (flexibly dosed from 10 to 20 mg/d) versus placebo in adults with PTSD. The primary outcome was change from baseline in the past-month version of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), analyzed using a mixed-model repeated-measures analysis of variance.

Findings/results: Forty-one patients were randomized, and 32 (78%) completed the 12 weeks of treatment. The mean reduction in CAPS-5 scores at week 12 did not significantly differ between the 2 arms; the effect size for the difference in changes between vortioxetine and placebo on CAPS-5 total scores at week 12 was Cohen d = 0.29. However, at week 8, the drug-placebo difference was d = 0.78, which met the multivariate criteria for statistical significance, P = 0.014.

Implications/conclusions: In this study of 41 patients, vortioxetine did not demonstrate superiority over placebo for adults with PTSD. Future PTSD trials may benefit from stratifying the randomization based on number of years since the index traumatic event and a history of failure to respond to treatment.
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http://dx.doi.org/10.1097/JCP.0000000000001363DOI Listing
February 2021

Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation.

Sci Adv 2021 Jan 27;7(5). Epub 2021 Jan 27.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Bavaria 80804, Germany.

Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type-specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing's syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism's nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.
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http://dx.doi.org/10.1126/sciadv.abe4497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840126PMC
January 2021

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.

Transl Psychiatry 2021 02 1;11(1):88. Epub 2021 Feb 1.

Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804, Munich, Germany.

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.
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http://dx.doi.org/10.1038/s41398-020-01147-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851167PMC
February 2021

Childhood maltreatment, prefrontal-paralimbic gray matter volume, and substance use in young adults and interactions with risk for bipolar disorder.

Sci Rep 2021 01 8;11(1):123. Epub 2021 Jan 8.

Department of Psychiatry and Behavioral Sciences, Dell Medical School, University of Texas at Austin, 1601 Trinity Street, Stop Z0600, Health Discovery Building, Austin, TX, 78712, USA.

Childhood maltreatment is associated with adverse effects on the brain, and an increased risk for psychopathology, including mood and substance use disorders. Individuals vary on the degree to which they exhibit neurobiological and clinical differences following maltreatment. Individuals with bipolar disorder exhibit greater magnitude of maltreatment-related prefrontal-paralimbic gray matter volume (GMV) deficits compared to typically developing individuals. It is unclear if greater structural differences stem from greater neural vulnerability to maltreatment in bipolar disorder, or if they relate to presence of other clinical features associated with childhood maltreatment, e.g., elevated prevalence of comorbid substance use disorders. To investigate this, we compared young adults with a family history of bipolar disorder (n = 21), but who did not fulfill diagnostic criteria for bipolar disorder, with typically developing young adults without a family history of bipolar disorder (n = 26). Participants completed structural neuroimaging, clinical and family history interviews, and assessment of childhood maltreatment and recent alcohol and cannabis use patterns. We examined relations between childhood maltreatment and prefrontal-paralimbic GMV by modeling main effects of maltreatment and family history group by maltreatment interactions on prefrontal-paralimbic GMV. We also examined relations between maltreatment and associated GMV changes with recent alcohol and cannabis use. Childhood maltreatment correlated with lower ventral, rostral and dorsolateral prefrontal and insular cortical GMV across all participants regardless of the presence or absence of familial history of bipolar disorder. However, exploratory analyses did reveal greater maltreatment-related GMV differences in individuals with prodromal symptoms of depression. Lower insula GMV was associated with greater frequency of cannabis use across all participants and greater quantity of alcohol use only in those with familial risk for bipolar disorder. Results suggest familial risk for bipolar disorder, and presumably genetic risk, may relate to outcomes following childhood maltreatment and should be considered in prevention/early intervention strategies.
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http://dx.doi.org/10.1038/s41598-020-80407-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794246PMC
January 2021

Transcription Factor Motifs Associated with Anterior Insula Gene Expression Underlying Mood Disorder Phenotypes.

Mol Neurobiol 2021 May 7;58(5):1978-1989. Epub 2021 Jan 7.

Department of Psychiatry, Dell Medical School, University of Texas at Austin, Austin, TX, USA.

Mood disorders represent a major cause of morbidity and mortality worldwide but the brain-related molecular pathophysiology in mood disorders remains largely undefined. Because the anterior insula is reduced in volume in patients with mood disorders, RNA was extracted from the anterior insula postmortem anterior insula of mood disorder samples and compared with unaffected controls for RNA-sequencing identification of differentially expressed genes (DEGs) in (a) bipolar disorder (BD; n = 37) versus (vs.) controls (n = 33), and (b) major depressive disorder (MDD n = 30) vs. controls, and (c) low vs. high axis I comorbidity (a measure of cumulative psychiatric disease burden). Given the regulatory role of transcription factors (TFs) in gene expression via specific-DNA-binding domains (motifs), we used JASPAR TF binding database to identify TF-motifs. We found that DEGs in BD vs. controls, MDD vs. controls, and high vs. low axis I comorbidity were associated with TF-motifs that are known to regulate expression of toll-like receptor genes, cellular homeostatic-control genes, and genes involved in embryonic, cellular/organ, and brain development. Robust imaging-guided transcriptomics by using meta-analytic imaging results to guide independent postmortem dissection for RNA-sequencing was applied by targeting the gray matter volume reduction in the anterior insula in mood disorders, to guide independent postmortem identification of TF motifs regulating DEG. Our findings of TF-motifs that regulate the expression of immune, cellular homeostatic-control, and developmental genes provide novel information about the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate underlying neuroanatomical phenotypes in mood disorders.
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http://dx.doi.org/10.1007/s12035-020-02195-8DOI Listing
May 2021

Neuroimaging Biomarkers in Schizophrenia.

Am J Psychiatry 2021 06 5;178(6):509-521. Epub 2021 Jan 5.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham (Kraguljac); Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta (McDonald); Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis (Widge); Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif., and Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif. (Rodriguez); Department of Psychiatry and Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque (Tohen); Department of Psychiatry, University of Texas Dell Medical School, Austin (Nemeroff).

Schizophrenia is a complex neuropsychiatric syndrome with a heterogeneous genetic, neurobiological, and phenotypic profile. Currently, no objective biological measures-that is, biomarkers-are available to inform diagnostic or treatment decisions. Neuroimaging is well positioned for biomarker development in schizophrenia, as it may capture phenotypic variations in molecular and cellular disease targets, or in brain circuits. These mechanistically based biomarkers may represent a direct measure of the pathophysiological underpinnings of the disease process and thus could serve as true intermediate or surrogate endpoints. Effective biomarkers could validate new treatment targets or pathways, predict response, aid in selection of patients for therapy, determine treatment regimens, and provide a rationale for personalized treatments. In this review, the authors discuss a range of mechanistically plausible neuroimaging biomarker candidates, including dopamine hyperactivity, -methyl-d-aspartate receptor hypofunction, hippocampal hyperactivity, immune dysregulation, dysconnectivity, and cortical gray matter volume loss. They then focus on the putative neuroimaging biomarkers for disease risk, diagnosis, target engagement, and treatment response in schizophrenia. Finally, they highlight areas of unmet need and discuss strategies to advance biomarker development.
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http://dx.doi.org/10.1176/appi.ajp.2020.20030340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222104PMC
June 2021

Screening for Adverse Childhood Experiences.

JAMA 2020 11;324(17):1789

retired, La Jolla, California.

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http://dx.doi.org/10.1001/jama.2020.16449DOI Listing
November 2020

Social media recruitment for mental health research: A systematic review.

Compr Psychiatry 2020 11 12;103:152197. Epub 2020 Aug 12.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. Electronic address:

Background: Social media holds exciting promise for advancing mental health research recruitment, however, the extent and efficacy to which these platforms are currently in use are underexplored.

Objective: A systematic review was conducted to characterize the current use and efficacy of social media in recruiting participants for mental health research.

Method: A literature review was performed using MEDLINE, EMBASE, and PsychINFO. Only non-duplicative manuscripts written in the English language and published between 1/1/2004-3/31/2019 were selected for further screening. Data extracted included study type and design, participant inclusion criteria, social media platform, advertising strategy, final recruited sample size, recruitment location, year, monetary incentives, comparison to other recruitment methods if performed, and final cost per participant.

Results: A total of 176 unique studies that used social media for mental health research recruitment were reviewed. The majority of studies were cross-sectional (62.5%) in design and recruited adults. Facebook was overwhelmingly the recruitment platform of choice (92.6%), with the use of paid advertisements being the predominant strategy (60.8%). Of the reviewed studies, substance abuse (43.8%) and mood disorders (15.3%) were the primary subjects of investigation. In 68.3% of studies, social media recruitment performed as well as or better than traditional recruitment methods in the number and cost of final enrolled participants. The majority of studies used Facebook for recruitment at a median cost per final recruited study participant of $19.47. In 55.6% of the studies, social media recruitment was the more cost-effective recruitment method when compared to traditional methods (e.g., referrals, mailing).

Conclusion: Social media appears to be an effective and economical recruitment tool for mental health research. The platform raises methodological and privacy concerns not covered in current research regulations that warrant additional consideration.
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http://dx.doi.org/10.1016/j.comppsych.2020.152197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704547PMC
November 2020

Insular functional alterations in emotional processing of schizophrenia patients revealed by Multivariate Pattern Analysis fMRI.

J Psychiatr Res 2020 11 1;130:128-136. Epub 2020 Aug 1.

FLENI-CONICET, Montañeses 2325, C1428AQK, Buenos Aires, Argentina; Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón I, Ciudad Universitaria, 1428, Buenos Aires, Argentina. Electronic address:

Emotion perception is impaired in schizophrenia patients (SP) and related to reduced social skills performance. There is a remarkable variability across subjects for functional neuroimaging alterations related to this phenomenon. In contrast to the univariate approaches of fMRI, Multivariate Pattern Analysis (MVPA) maintains the within-subject voxel-level variability. The purpose of this study was to assess emotion processing in SP, in previously identified ROIs -i.e. amygdala, hippocampus, insula, and thalamus-, while retaining the functional heterogeneity that may exist between subjects. We evaluated 23 SP and 23 healthy controls (HC). Happy, sad, and neutral faces were presented. A single trial fMRI model was applied. Patterns of activation within each ROI were classified at the subject level. Within each group, stimuli classification scores were tested against random label classification scores. In ROIs with significant results, a whole ROI classification was performed, to test whether en bloc stimuli discrimination was present. A between-group analysis was conducted also. For the classification of stimuli above chance, in the HC results were significant in the left insula in all of the stimuli dichotomies, but were non-significant in SP for happy vs. sad. In whole ROI classification, SP had significant results in bilateral insular cortex for happy vs. neutral. The left amygdala showed diminished stimuli classification scores in SP for sad vs. neutral. In conclusion, MVPA seems useful to study emotional processing in schizophrenia. In SP, either en bloc or no stimuli discrimination was seen in the insula, and reduced stimuli discrimination was seen in the left amygdala.
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http://dx.doi.org/10.1016/j.jpsychires.2020.06.017DOI Listing
November 2020

Prior trauma-related experiences predict the development of posttraumatic stress disorder after a new traumatic event.

Depress Anxiety 2021 01 12;38(1):40-47. Epub 2020 Aug 12.

Department of Psychiatry, Dell Medical School, University of Texas at Austin, Austin, Texas.

Background: Many reports have documented the relationship between previous traumatic experiences, including childhood trauma, and the development of later life psychopathology, including posttraumatic stress disorder (PTSD). Identification of individuals at greatest risk for the development of PTSD could lead to preventative interventions. The present study examined the developmental course of PTSD after trauma exposure, using histories of previous traumatic experiences and the severity of the reaction to the trauma as predictors.

Methods: Participants (N = 713) were recruited from Emergency Departments in Miami and Atlanta immediately following a traumatic experience. Histories of previous traumatic experiences and the immediate reaction to the new trauma were examined at baseline. Follow-up assessments of PTSD severity were conducted at 1, 3, and 6 months.

Results: Histories of child abuse and pre-existing trauma symptoms predicted the immediate response to stress (R  = .21, p < .001) and the initial trauma reaction (p < .005).) A mixed-model repeated-measures analysis of variance found that immediate stress response and a history of prior trauma (p < .001) significantly predicted the course of PTSD symptoms. Area under the curve (AUC) analyses suggested that the presence of PTSD at each successive assessment was predicted most substantially by the severity of PTSD at the immediately prior follow-up assessment (AUC > 0.86).

Conclusions: The current findings suggest that previous traumatic experiences lead to a greater immediate reaction to trauma and combine to predict the development of PTSD, the maintenance of which is not moderated by these earlier experiences. The identification of people likely to develop PTSD may be aided by the assessment of prior experiences and immediate reactions.
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http://dx.doi.org/10.1002/da.23084DOI Listing
January 2021

The Moderating Effect of Resilience on the Relationship between Adverse Childhood Experiences (ACEs) and Quality of Physical and Mental Health among Adult Sexual and Gender Minorities.

Behav Med 2020 Jul-Sep;46(3-4):366-374

Department of Psychiatry, Dell Medical School, The University of Texas at Austin.

Sexual and gender minority (SGM) individuals experience a greater burden of poor mental health compared to heterosexual individuals. One factor that helps to explain this disparity is trauma experienced during childhood. SGM are more likely to report traumatic experiences during childhood contributing to this disparity. Previous research has shown that resilience moderates the relationship between childhood trauma and adults mental health outcomes. As part of the Strengthening Colors of Pride project, data on 463 SGM adults living in San Antonio were collected using surveys. A diverse recruitment strategy was used in conjunction with a community advisory board. The brief resilience scale (BRS) was used to assess intrapersonal level resilience to determine if there was an effect on the relationship between ACEs and quality of mental and physical health. Differences were noted for some items across low, normal, and high levels of resilience. Both ACEs and BRS significantly predicted quality of mental and physical health. We also noted a significant interaction between ACEs and BRS with regard to quality of mental health. Findings suggest there is a relationship between intrapersonal level resilience, ACEs, and quality of mental health.
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http://dx.doi.org/10.1080/08964289.2020.1727406DOI Listing
August 2020

The Moderating Effect of Resilience on the Relationship between Adverse Childhood Experiences (ACEs) and Quality of Physical and Mental Health among Adult Sexual and Gender Minorities.

Behav Med 2020 Jul-Sep;46(3-4):366-374

Department of Psychiatry, Dell Medical School, The University of Texas at Austin.

Sexual and gender minority (SGM) individuals experience a greater burden of poor mental health compared to heterosexual individuals. One factor that helps to explain this disparity is trauma experienced during childhood. SGM are more likely to report traumatic experiences during childhood contributing to this disparity. Previous research has shown that resilience moderates the relationship between childhood trauma and adults mental health outcomes. As part of the Strengthening Colors of Pride project, data on 463 SGM adults living in San Antonio were collected using surveys. A diverse recruitment strategy was used in conjunction with a community advisory board. The brief resilience scale (BRS) was used to assess intrapersonal level resilience to determine if there was an effect on the relationship between ACEs and quality of mental and physical health. Differences were noted for some items across low, normal, and high levels of resilience. Both ACEs and BRS significantly predicted quality of mental and physical health. We also noted a significant interaction between ACEs and BRS with regard to quality of mental health. Findings suggest there is a relationship between intrapersonal level resilience, ACEs, and quality of mental health.
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http://dx.doi.org/10.1080/08964289.2020.1727406DOI Listing
August 2020

Identification of a Signaling Mechanism by Which the Microbiome Regulates Th17 Cell-Mediated Depressive-Like Behaviors in Mice.

Am J Psychiatry 2020 10 31;177(10):974-990. Epub 2020 Jul 31.

Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff).

Objective: Microbiota dysbiosis has been linked to major depressive disorder, but the mechanisms whereby the microbiota modulates mood remain poorly understood. The authors tested whether specific changes in the microbiome modulate depressive-like behaviors.

Methods: Stools from learned helpless, non-learned helpless, and non-shocked mice were analyzed by V4 16S RNA sequencing to identify gut bacteria associated with learned helplessness and to quantify the level of the quorum-sensing molecule autoinducer-2 (AI-2). T cells were analyzed by flow cytometry, and serum amyloid proteins (SAA) were analyzed by quantitative real-time polymerase chain reaction. Fecal transfer approach and administration of oleic acid and AI-2 were used to determine the effects of the microbiome and quorum-sensing molecules on depressive-like behaviors.

Results: Mice deficient in segmented filamentous bacteria (SFB) were resilient to the induction of depressive-like behavior, and were resensitized when SFB was reintroduced in the gut. SFB produces the quorum-sensing AI-2 and promotes the production of SAA1 and SAA2 by the host, which increases T helper 17 (Th17) cell production. Th17 cells were required to promote depressive-like behaviors by AI-2, as AI-2 administration did not promote susceptibility to depressive-like behaviors or SAA1 and SAA2 production in Th17-deficient mice after stress. Oleic acid, an AI-2 inhibitor, exhibited antidepressant properties, reducing depressive-like behavior, intestinal SAA1 and SAA2 production, and hippocampal Th17 cell accumulation. Stool samples from 10 people with current depressive symptoms and 10 matched healthy control subjects were analyzed as well. Patients with current major depressive disorder exhibited increased fecal interleukin 17A, SAA, and SFB levels.

Conclusions: The study results reveal a novel mechanism by which bacteria alter mood.
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http://dx.doi.org/10.1176/appi.ajp.2020.19090960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647050PMC
October 2020

A health care workers mental health crisis line in the age of COVID-19.

Depress Anxiety 2020 08 15;37(8):822-826. Epub 2020 Jul 15.

Department of Psychiatry and Behavioral Sciences, Dell Medical School, University of Texas, Austin, Texas.

Introduction: The COVID-19 pandemic has brought a health care crisis of unparalleled devastation. A mental health crisis as a second wave has begun to emerge in our front-line health care workers.

Objective: To address these needs, The Healthcare Worker Mental Health COVID-19 Hotline, based on crisis intervention principles, was developed and launched in 2 weeks.

Methods: Upon reflection of why this worked, we decided it might be useful to describe what we now recognize as 13-steps which led to our success. The process included the following: (1) anticipate mental health needs; (2) use leadership capable of mobilizing the systems and resources; (3) convene a multidisciplinary team; (4) delegate tasks and set timelines; (5) choose a clinical service model; (6) motivate staff as a workforce of volunteers; (7) develop training and educational materials; (8) develop personal, local, and national resources; (9) develop marketing plans; (10) deliver the training; (11) launch a 24 hr/7days per week Healthcare Worker Mental Health COVID-19 Hotline, and launch follow-up sessions for staff; (12) structure data collection to determine effectiveness and outcomes; and (13) obtain funding (not required).

Discussion: We believe the process we used is specifically useful for others who may want to develop a COVID-19 hotline services for health care workers and generally useful for the development of other mental health services.

Conclusion: We hope that this process may serve as a guide for other heath care systems.
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http://dx.doi.org/10.1002/da.23073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405037PMC
August 2020

A validated predictive algorithm of post-traumatic stress course following emergency department admission after a traumatic stressor.

Nat Med 2020 07 6;26(7):1084-1088. Epub 2020 Jul 6.

Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.

Annually, approximately 30 million patients are discharged from the emergency department (ED) after a traumatic event. These patients are at substantial psychiatric risk, with approximately 10-20% developing one or more disorders, including anxiety, depression or post-traumatic stress disorder (PTSD). At present, no accurate method exists to predict the development of PTSD symptoms upon ED admission after trauma. Accurate risk identification at the point of treatment by ED services is necessary to inform the targeted deployment of existing treatment to mitigate subsequent psychopathology in high-risk populations. This work reports the development and validation of an algorithm for prediction of post-traumatic stress course over 12 months using two independently collected prospective cohorts of trauma survivors from two level 1 emergency trauma centers, which uses routinely collectible data from electronic medical records, along with brief clinical assessments of the patient's immediate stress reaction. Results demonstrate externally validated accuracy to discriminate PTSD risk with high precision. While the predictive algorithm yields useful reproducible results on two independent prospective cohorts of ED patients, future research should extend the generalizability to the broad, clinically heterogeneous ED population under conditions of routine medical care.
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http://dx.doi.org/10.1038/s41591-020-0951-zDOI Listing
July 2020

The Bidirectional Relationship of Depression and Inflammation: Double Trouble.

Neuron 2020 07 17;107(2):234-256. Epub 2020 Jun 17.

Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School, Austin, TX 78712, USA. Electronic address:

Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory processes have been implicated in the pathophysiology of depression. It is now well established that dysregulation of both the innate and adaptive immune systems occur in depressed patients and hinder favorable prognosis, including antidepressant responses. In this review, we describe how the immune system regulates mood and the potential causes of the dysregulated inflammatory responses in depressed patients. However, the proportion of never-treated major depressive disorder (MDD) patients who exhibit inflammation remains to be clarified, as the heterogeneity in inflammation findings may stem in part from examining MDD patients with varied interventions. Inflammation is likely a critical disease modifier, promoting susceptibility to depression. Controlling inflammation might provide an overall therapeutic benefit, regardless of whether it is secondary to early life trauma, a more acute stress response, microbiome alterations, a genetic diathesis, or a combination of these and other factors.
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http://dx.doi.org/10.1016/j.neuron.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381373PMC
July 2020

Efficacy and safety of TS-121, a novel vasopressin V receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study.

J Psychiatr Res 2020 09 31;128:43-51. Epub 2020 May 31.

Taisho Pharmaceutical Co., Ltd., Development Headquarters, 3-24-1 Takada, Toshima-ku, Tokyo, 170-8633, Japan.

Vasopressin 1B (V) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018. The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD.
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http://dx.doi.org/10.1016/j.jpsychires.2020.05.017DOI Listing
September 2020

Pharmacological Treatment of Anxiety Disorders: The Role of the HPA Axis.

Front Psychiatry 2020 15;11:443. Epub 2020 May 15.

Department of Psychiatry, University of Texas at Austin, Austin, TX, United States.

Stress in general, and early life stress in particular, has been associated with the development of anxiety and mood disorders. The molecular, biological and psychological links between stress exposure and the pathogenesis of anxiety and mood disorders have been extensively studied, resulting in the search of novel psychopharmacological strategies aimed at targets of the hypothalamic-pituitary-adrenal (HPA) axis. Hyperactivity of the HPA axis has been observed in certain subgroups of patients with anxiety and mood disorders. In addition, the effects of different anti-anxiety agents on various components of the HPA axis has been investigated, including benzodiazepines, tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs). For example, benzodiazepines, including clonazepam and alprazolam, have been demonstrated to reduce the activity of corticotrophin releasing factor (CRF) neurons in the hypothalamus. TCAs and SSRIs are also effective anti-anxiety agents and these may act, in part, by modulating the HPA axis. In this regard, the SSRI escitalopram inhibits CRF release in the central nucleus of the amygdala, while increasing glucocorticoid receptor (GRs) density in the hippocampus and hypothalamus. The molecular effects of these anti-anxiety agents in the regulation of the HPA axis, taken together with their clinical efficacy, may provide further understanding about the role of the HPA axis in the pathophysiology of mood and anxiety disorders, paving the way for the development of novel therapeutic strategies.
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http://dx.doi.org/10.3389/fpsyt.2020.00443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243209PMC
May 2020

Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry.

BMC Med 2020 06 5;18(1):170. Epub 2020 Jun 5.

Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804, Munich, Germany.

Background: Antidepressant medication (ADM) and psychotherapy are effective treatments for major depressive disorder (MDD). It is unclear, however, if treatments differ in their effectiveness at the symptom level and whether symptom information can be utilised to inform treatment allocation. The present study synthesises comparative effectiveness information from randomised controlled trials (RCTs) of ADM versus psychotherapy for MDD at the symptom level and develops and tests the Symptom-Oriented Therapy (SOrT) metric for precision treatment allocation.

Methods: First, we conducted systematic review and meta-analyses of RCTs comparing ADM and psychotherapy at the individual symptom level. We searched PubMed Medline, PsycINFO, and the Cochrane Central Register of Controlled Trials databases, a database specific for psychotherapy RCTs, and looked for unpublished RCTs. Random-effects meta-analyses were applied on sum-scores and for individual symptoms for the Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI) measures. Second, we computed the SOrT metric, which combines meta-analytic effect sizes with patients' symptom profiles. The SOrT metric was evaluated using data from the Munich Antidepressant Response Signature (MARS) study (n = 407) and the Emory Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study (n = 234).

Results: The systematic review identified 38 RCTs for qualitative inclusion, 27 and 19 for quantitative inclusion at the sum-score level, and 9 and 4 for quantitative inclusion on individual symptom level for the HAM-D and BDI, respectively. Neither meta-analytic strategy revealed significant differences in the effectiveness of ADM and psychotherapy across the two depression measures. The SOrT metric did not show meaningful associations with other clinical variables in the MARS sample, and there was no indication of utility of the metric for better treatment allocation from PReDICT data.

Conclusions: This registered report showed no differences of ADM and psychotherapy for the treatment of MDD at sum-score and symptom levels. Symptom-based metrics such as the proposed SOrT metric do not inform allocation to these treatments, but predictive value of symptom information requires further testing for other treatment comparisons.
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http://dx.doi.org/10.1186/s12916-020-01623-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273646PMC
June 2020

Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry.

BMC Med 2020 06 5;18(1):170. Epub 2020 Jun 5.

Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804, Munich, Germany.

Background: Antidepressant medication (ADM) and psychotherapy are effective treatments for major depressive disorder (MDD). It is unclear, however, if treatments differ in their effectiveness at the symptom level and whether symptom information can be utilised to inform treatment allocation. The present study synthesises comparative effectiveness information from randomised controlled trials (RCTs) of ADM versus psychotherapy for MDD at the symptom level and develops and tests the Symptom-Oriented Therapy (SOrT) metric for precision treatment allocation.

Methods: First, we conducted systematic review and meta-analyses of RCTs comparing ADM and psychotherapy at the individual symptom level. We searched PubMed Medline, PsycINFO, and the Cochrane Central Register of Controlled Trials databases, a database specific for psychotherapy RCTs, and looked for unpublished RCTs. Random-effects meta-analyses were applied on sum-scores and for individual symptoms for the Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI) measures. Second, we computed the SOrT metric, which combines meta-analytic effect sizes with patients' symptom profiles. The SOrT metric was evaluated using data from the Munich Antidepressant Response Signature (MARS) study (n = 407) and the Emory Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study (n = 234).

Results: The systematic review identified 38 RCTs for qualitative inclusion, 27 and 19 for quantitative inclusion at the sum-score level, and 9 and 4 for quantitative inclusion on individual symptom level for the HAM-D and BDI, respectively. Neither meta-analytic strategy revealed significant differences in the effectiveness of ADM and psychotherapy across the two depression measures. The SOrT metric did not show meaningful associations with other clinical variables in the MARS sample, and there was no indication of utility of the metric for better treatment allocation from PReDICT data.

Conclusions: This registered report showed no differences of ADM and psychotherapy for the treatment of MDD at sum-score and symptom levels. Symptom-based metrics such as the proposed SOrT metric do not inform allocation to these treatments, but predictive value of symptom information requires further testing for other treatment comparisons.
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http://dx.doi.org/10.1186/s12916-020-01623-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273646PMC
June 2020

Hormonal Treatments for Major Depressive Disorder: State of the Art.

Am J Psychiatry 2020 08 27;177(8):686-705. Epub 2020 May 27.

Child Study Center and Department of Radiology and Biomedical Imaging, Yale University, New Haven, Conn. (Dwyer); Department of Psychiatry, Case Western Reserve University, Cleveland, and Northcoast Behavioral Healthcare Hospital, Northfield, Ohio (Aftab); Yale School of Medicine, New Haven, Conn. (Radhakrishnan); Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis (Widge); Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif., and VA Palo Alto Health Care System, Palo Alto, Calif. (Rodriguez); Department of Psychiatry and Human Behavior, Butler Hospital, Brown University, Providence, R.I. (Carpenter); Department of Psychiatry, University of Texas at Austin (Nemeroff); Department of Psychiatry and Human Behavior, Emory University School of Medicine, Atlanta (McDonald); and Department of Psychiatry, University of Wisconsin-Madison (Kalin).

Major depressive disorder is a common psychiatric disorder associated with marked suffering, morbidity, mortality, and cost. The World Health Organization projects that by 2030, major depression will be the leading cause of disease burden worldwide. While numerous treatments for major depression exist, many patients do not respond adequately to traditional antidepressants. Thus, more effective treatments for major depression are needed, and targeting certain hormonal systems is a conceptually based approach that has shown promise in the treatment of this disorder. A number of hormones and hormone-manipulating compounds have been evaluated as monotherapies or adjunctive treatments for major depression, with therapeutic actions attributable not only to the modulation of endocrine systems in the periphery but also to the CNS effects of hormones on non-endocrine brain circuitry. The authors describe the physiology of the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary thyroid (HPT), and hypothalamic-pituitary-gonadal (HPG) axes and review the evidence for selected hormone-based interventions for the treatment of depression in order to provide an update on the state of this field for clinicians and researchers. The review focuses on the HPA axis-based interventions of corticotropin-releasing factor antagonists and the glucocorticoid receptor antagonist mifepristone, the HPT axis-based treatments of thyroid hormones (T and T), and the HPG axis-based treatments of estrogen replacement therapy, the progesterone derivative allopregnanolone, and testosterone. While some treatments have largely failed to translate from preclinical studies, others have shown promising initial results and represent active fields of study in the search for novel effective treatments for major depression.
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http://dx.doi.org/10.1176/appi.ajp.2020.19080848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841732PMC
August 2020

Implementation of Advanced Methods for Reproductive Pharmacovigilance in Autism: A Meta-Analysis of the Effects of Prenatal Antidepressant Exposure.

Am J Psychiatry 2020 06 7;177(6):506-517. Epub 2020 May 7.

Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami (Vega, Bozhdaraj, Saltz); Department of Psychology, University of South Florida St. Petersburg (G.C. Newport); Department of Psychiatry (Nemeroff, D.J. Newport), University of Texas at Austin Dell Medical School, Austin.

Objective: Observational studies of prenatal antidepressant safety are hindered by methodological concerns, including susceptibility to surveillance bias. Some studies address potential bias by using alternative strategies to operationalize study comparison groups. In a meta-analysis of the association between prenatal antidepressant exposure and autism risk, the authors examined the utility of comparison group operationalization in reducing surveillance bias.

Methods: A systematic search of multiple databases through August 2017 was conducted, selecting controlled observational studies of the association of prenatal antidepressant exposure with autism. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analysis produced summary effect measures with 95% confidence intervals stratified by comparator group composition, antidepressant class, and trimester of exposure.

Results: Fourteen studies were included, with 13 reporting results using a population-based comparison group, five using a psychiatric control group, and four using a discordant-sibling control group. Eight of the 14 studies were rated poor because of inadequate control for prenatal depression and maternal ethnicity. Autism risk estimates after prenatal exposure to any antidepressant were decidedly different for population-based designs (hazard ratio=1.42, 95% CI=1.18, 1.70; odds ratio=1.58, 95% CI=1.25, 1.99) compared with psychiatric control (hazard ratio=1.14, 95% CI=0.84, 1.53; odds ratio=1.24, 95% CI=0.93, 1.66) and discordant-sibling (hazard ratio=0.97, 95% CI=0.68, 1.37; odds ratio=0.85, 95% CI=0.54, 1.35) designs. Findings for prenatal exposure to selective serotonin reuptake inhibitors were similar. Meta-regression of population-based studies demonstrated that despite statistical adjustment, ethnicity differences remained a significant source of study heterogeneity.

Conclusions: In this meta-analysis, neither psychiatric control nor discordant-sibling designs supported an association between prenatal antidepressant exposure and autism. Discordant-sibling designs effectively addressed surveillance bias in pharmacovigilance reports derived from national registries and other large databases.
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http://dx.doi.org/10.1176/appi.ajp.2020.18070766DOI Listing
June 2020
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