Publications by authors named "Linda L Carpenter"

155 Publications

Audio-Guided Mindfulness Meditation During Transcranial Magnetic Stimulation Sessions for the Treatment of Major Depressive Disorder: A Pilot Feasibility Study.

Front Psychol 2021 17;12:678911. Epub 2021 Aug 17.

Butler Hospital TMS Clinic and Neuromodulation Research Facility, Providence, RI, United States.

Mindfulness-Based Cognitive Therapy (MBCT) has been shown to enhance the long-term treatment outcomes for major depressive disorder (MDD), and engagement of specific brain activities during brain stimulation may produce synergistic effects. Audio-guided meditation exercises are a component of MBCT that might be combined with standard transcranial magnetic stimulation (TMS) therapy sessions. We developed and pilot-tested a modified MBCT protocol for patients undergoing a standard course of TMS for MDD. Four MBCT audiotracks with differing durations and types of mental focus were selected. Patients listened to the audiotapes through headphones during daily TMS sessions for 5 consecutive weeks. The primary goal was to evaluate the feasibility and acceptability of the meditation intervention with TMS. Changes in self-rated measures of symptom severity, stress, life satisfaction, and mindfulness were also assessed. Seventeen depressed subjects completed the study and 12 terminated early. Reasons for discontinuation included an inability to meditate in the treatment setting and induction of negative mood states. TMS percussive sensations and clicking sounds hindered the ability of patients to fully concentrate on or hear the voice of the audiotape narrator. Some became overwhelmed or felt increased pressure, anxiety, or aggravation trying to do meditation exercises while receiving TMS. There is a growing interest in combining TMS with other concurrent psychotherapeutic interventions to optimize treatment outcomes. The results highlight numerous feasibility issues with MBCT guided audiotapes during TMS treatment. Future work should draw on these shortcomings to evaluate the appropriateness of MBCT for depressed patients undergoing neuromodulation.
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http://dx.doi.org/10.3389/fpsyg.2021.678911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415877PMC
August 2021

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

Effects of transcranial magnetic stimulation on anhedonia in treatment resistant major depressive disorder.

Brain Behav 2021 Sep 28;11(9):e2329. Epub 2021 Aug 28.

Butler Hospital TMS Clinic and Neuromodulation Research Facility, Providence, Rhode Island, USA.

Background: Anhedonia is one of the defining features of depression but it remains difficult to target and treat. Transcranial magnetic stimulation (TMS) is a proven treatment for depression, but its effects on anhedonia and whether anhedonia can be used as a predictive biomarker of response is not well known.

Methods: Snaith-Hamilton Pleasure Scale was administered to patients with depression before and after a standard course of TMS in a naturalistic outpatient setting.

Results: 144 patients were analyzed. There was an overall significant improvement in anhedonia from pre- to post-treatment (7.69 ± 3.88 vs. 2.96 ± 3.45; p < .001). Significant correlations between improvements in anhedonia and other depressive symptoms were present (r = 0.55, p < .001). Logistic regression revealed that baseline anhedonia severity was not a significant predictor of clinical outcome.

Conclusion: This is the first large, naturalistic study examining the effects of standard, non-research TMS on anhedonia. Among depressed patients, TMS resulted in significant improvements in anhedonia. Patients with severe baseline anhedonia had an equal chance of achieving clinical response/remission. Patients with anhedonia should not be excluded from treatment if they are safe for outpatient care and otherwise appropriate candidates for treatment.
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http://dx.doi.org/10.1002/brb3.2329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442591PMC
September 2021

Effects of single-dose L-theanine on motor cortex excitability.

Clin Neurophysiol 2021 Sep 10;132(9):2062-2064. Epub 2021 Jul 10.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Butler Hospital, Providence, RI, USA.

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http://dx.doi.org/10.1016/j.clinph.2021.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384717PMC
September 2021

Theta burst stimulation for the acute treatment of major depressive disorder: A systematic review and meta-analysis.

Transl Psychiatry 2021 05 28;11(1):330. Epub 2021 May 28.

Brown University Department of Psychiatry and Human Behavior, Butler Hospital TMS Clinic and Neuromodulation Research Facility, Los Angeles, USA.

Patients with major depressive disorder (MDD) may be refractory to or have contraindications that preclude treatment with antidepressant pharmacotherapies. Alternative therapies such as repetitive transcranial magnetic stimulation (rTMS) continue to evolve, and include theta burst stimulation (TBS), which has advantages over conventional rTMS. The aim of this study was to identify and meta-analyze efficacy data from all randomized controlled trials (RCTs) investigating TBS as a treatment for MDD. Published reports of RCTs (January 1, 2010 to October 23, 2020) were identified via systematic searches in computerized databases, followed by review of individual reports for inclusion. Inclusion criteria included primary diagnosis of MDD ≥ 1 week duration of therapy with ≥10 sessions, and treatment with any form of TBS. The Cochrane GRADE methodology and PRISMA criteria were used for evaluation of individual trials. Data from ten RCTs were included, representing 667 patients. Of these, 8 RCTs compared TBS to sham treatment and one compared TBS to standard rTMS (i.e., high frequency stimulation over left dorsolateral prefrontal cortex [HFL]). Quality of evidence assessment yielded high confidence in the finding of TBS being superior to sham on response measured by the Hamilton Depression Rating Scale (HRSD) (RR = 2.4; 95% CI: 1.27 to 4.55; P = 0.007; I = 40%). Comparison of HRSD response rates for TBS versus rTMS produced no statistically significant difference (RR = 1.02; 95% CI: 0.85 to 1.23; P = 0.80; I = 0%). The incidence of adverse events between TBS and rTMS was not statistically different. The findings of a positive effect of TBS vs. sham, and noninferiority of TBS vs. standard HFL rTMS support the continued development of TBS to treat depression.
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http://dx.doi.org/10.1038/s41398-021-01441-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163818PMC
May 2021

Theta burst stimulation for the acute treatment of major depressive disorder: A systematic review and meta-analysis.

Transl Psychiatry 2021 05 28;11(1):330. Epub 2021 May 28.

Brown University Department of Psychiatry and Human Behavior, Butler Hospital TMS Clinic and Neuromodulation Research Facility, Los Angeles, USA.

Patients with major depressive disorder (MDD) may be refractory to or have contraindications that preclude treatment with antidepressant pharmacotherapies. Alternative therapies such as repetitive transcranial magnetic stimulation (rTMS) continue to evolve, and include theta burst stimulation (TBS), which has advantages over conventional rTMS. The aim of this study was to identify and meta-analyze efficacy data from all randomized controlled trials (RCTs) investigating TBS as a treatment for MDD. Published reports of RCTs (January 1, 2010 to October 23, 2020) were identified via systematic searches in computerized databases, followed by review of individual reports for inclusion. Inclusion criteria included primary diagnosis of MDD ≥ 1 week duration of therapy with ≥10 sessions, and treatment with any form of TBS. The Cochrane GRADE methodology and PRISMA criteria were used for evaluation of individual trials. Data from ten RCTs were included, representing 667 patients. Of these, 8 RCTs compared TBS to sham treatment and one compared TBS to standard rTMS (i.e., high frequency stimulation over left dorsolateral prefrontal cortex [HFL]). Quality of evidence assessment yielded high confidence in the finding of TBS being superior to sham on response measured by the Hamilton Depression Rating Scale (HRSD) (RR = 2.4; 95% CI: 1.27 to 4.55; P = 0.007; I = 40%). Comparison of HRSD response rates for TBS versus rTMS produced no statistically significant difference (RR = 1.02; 95% CI: 0.85 to 1.23; P = 0.80; I = 0%). The incidence of adverse events between TBS and rTMS was not statistically different. The findings of a positive effect of TBS vs. sham, and noninferiority of TBS vs. standard HFL rTMS support the continued development of TBS to treat depression.
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http://dx.doi.org/10.1038/s41398-021-01441-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163818PMC
May 2021

NMDA-receptor agonist reveals LTP-like properties of 10-Hz rTMS in the human motor cortex.

Brain Stimul 2021 May-Jun;14(3):619-621. Epub 2021 Mar 29.

Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.

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http://dx.doi.org/10.1016/j.brs.2021.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164996PMC
March 2021

NMDA-receptor agonist reveals LTP-like properties of 10-Hz rTMS in the human motor cortex.

Brain Stimul 2021 May-Jun;14(3):619-621. Epub 2021 Mar 29.

Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.

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http://dx.doi.org/10.1016/j.brs.2021.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164996PMC
March 2021

The COBRE Center for Neuromodulation (CCN) at Butler Hospital: Clinical-Translational Research in Human Brain Stimulation.

R I Med J (2013) 2021 Mar 1;104(2):30-33. Epub 2021 Mar 1.

Butler Hospital, Providence RI; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University.

The COBRE Center for Neuromodulation (CCN) at Butler Hospital supports clinical research in neuromodulation and investigators' career development in this field. The work couples brain stimulation methods with readouts of brain activity (e.g., using various neuroimaging, behavioral, and physiological assessment methods) in clinical or clinically relevant populations. Its guiding principle is that for noninvasive brain stimulation to gain efficacy and implementation, it is essential to better characterize clinically relevant target circuits and mechanisms of action. The CCN includes a Design and Analysis Core (DAC) to support rigorous and innovative experimental design and data analytic strategies and a Neuromodulation and Neuroimaging Core (NNC) to facilitate the acquisition and processing of high-quality data using noninvasive neurostimulation and neuroimaging methods. This article will describe the CCN's research focus and how it enhances research capacity in neuromodulation in our state. It will introduce our current investigator Project Leaders, their projects, and our pilot project program. It will also detail the CCN's links to Centers and research cores in Rhode Island researching allied areas of clinical neuroscience, neurology, psychiatry, and psychology, current collaborative efforts across those centers, and opportunities to collaborate in research and training.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211205PMC
March 2021

A preliminary investigation of childhood anxiety/depressive symptomatology and working memory across multiple units of analysis.

Psychiatry Res 2021 04 10;298:113786. Epub 2021 Feb 10.

Alpert Medical School of Brown University, Department of Psychiatry & Human Behavior, Providence, RI, USA.

This exploratory study examined multiple units of working memory (WM) analysis in a transdiagnostic, treatment-seeking, pediatric sample. This included a) an electroencephalography marker of WM (coupling of theta and gamma oscillations [i.e., theta-gamma coupling] in frontal brain regions), b) WM test performance, and c) parent-reported WM symptoms. A composite score combining each of these units of analysis correlated with self-reported depressive and anxiety symptoms, with only theta-gamma coupling independently predicted anxiety/depressive symptoms. Results confirm prior findings on the association between WM and anxiety/depression, although the majority of this variance was explained by frontal theta-gamma coupling during WM demands.
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http://dx.doi.org/10.1016/j.psychres.2021.113786DOI Listing
April 2021

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee.

Clin Neurophysiol 2021 03 3;132(3):819-837. Epub 2020 Dec 3.

Hinda and Arthur Marcus Institute for Aging Research and Deanna and Sidney Wolk Center for Memory Health, Hebrew SeniorLife and Department of Neurology, Harvard Medical School, Boston, MA, USA; Guttmann Brain Health Institute, Institut Guttmann, Universitat Autonoma, Barcelona, Spain. Electronic address:

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines.
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http://dx.doi.org/10.1016/j.clinph.2020.11.018DOI Listing
March 2021

Individual alpha frequency proximity associated with repetitive transcranial magnetic stimulation outcome: An independent replication study from the ICON-DB consortium.

Clin Neurophysiol 2021 02 10;132(2):643-649. Epub 2020 Nov 10.

Research Institute Brainclinics, Brainclinics Foundation, Nijmegen, the Netherlands; Dept. of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Location AMC, Amsterdam Neuroscience, Amsterdam, the Netherlands. Electronic address:

Objective: The aim of the current study was to attempt to replicate the finding that the individual alpha frequency (IAF) as well as the absolute difference between IAF and 10 Hz stimulation frequency (IAF-prox) is related to treatment outcome.

Methods: Correlations were performed to investigate the relationship between IAF-prox and percentage symptom improvement in a sample of 153 patients with major depressive disorder treated with 10 Hz (N = 59) to the left dorsolateral prefrontal cortex (DLPFC) or 1 Hz (N = 94) to the right DLPFC repetitive Transcranial Magnetic Stimulation (rTMS).

Results: There was a significant negative correlation between IAF-prox and the percentage of symptom improvement only for the 10 Hz group. Curve fitting models revealed that there was a quadratic association between IAF and treatment response in the 10 Hz group, with a peak at 10 Hz IAF.

Conclusion: The main result of Corlier and colleagues was replicated, and the findings suggest that the distance between 10 Hz stimulation frequency and the IAF may influence clinical outcome in a non-linear manner.

Significance: rTMS is often administered at a frequency of 10 Hz, which is the center of the EEG alpha frequency band. The results can make a significant contribution to optimizing the clinical application of rTMS.
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http://dx.doi.org/10.1016/j.clinph.2020.10.017DOI Listing
February 2021

Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines.

Clin Neurophysiol 2021 01 24;132(1):269-306. Epub 2020 Oct 24.

Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.
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http://dx.doi.org/10.1016/j.clinph.2020.10.003DOI Listing
January 2021

Resting EEG theta connectivity and alpha power to predict repetitive transcranial magnetic stimulation response in depression: A non-replication from the ICON-DB consortium.

Clin Neurophysiol 2021 02 10;132(2):650-659. Epub 2020 Nov 10.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare, The Epworth Clinic, Camberwell, Victoria 3004, Australia; Monash University, Department of Psychiatry, Central Clinical School, Commercial Rd, Melbourne, Victoria, Australia.

Objective: Our previous research showed high predictive accuracy at differentiating responders from non-responders to repetitive transcranial magnetic stimulation (rTMS) for depression using resting electroencephalography (EEG) and clinical data from baseline and one-week following treatment onset using a machine learning algorithm. In particular, theta (4-8 Hz) connectivity and alpha power (8-13 Hz) significantly differed between responders and non-responders. Independent replication is a necessary step before the application of potential predictors in clinical practice. This study attempted to replicate the results in an independent dataset.

Methods: We submitted baseline resting EEG data from an independent sample of participants who underwent rTMS treatment for depression (N = 193, 128 responders) (Krepel et al., 2018) to the same between group comparisons as our previous research (Bailey et al., 2019).

Results: Our previous results were not replicated, with no difference between responders and non-responders in theta connectivity (p = 0.250, Cohen's d = 0.1786) nor alpha power (p = 0.357, η = 0.005).

Conclusions: These results suggest that baseline resting EEG theta connectivity or alpha power are unlikely to be generalisable predictors of response to rTMS treatment for depression.

Significance: These results highlight the importance of independent replication, data sharing and using large datasets in the prediction of response research.
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http://dx.doi.org/10.1016/j.clinph.2020.10.018DOI Listing
February 2021

Double-blind, placebo-controlled, proof-of-concept trial of a kappa-selective opioid receptor antagonist augmentation in treatment-resistant depression.

Ann Clin Psychiatry 2020 02;32(4):18-26

Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114 USA. E-MAIL:

Background: Kappa-opioid antagonism may possess antidepressant properties. We assessed, in a proof-of-concept pilot trial among patients with major depressive disorder with inadequate response to antidepressants, the efficacy of adjunctive CERC-501 (formerly LY2456302), a kappaselective opioid receptor antagonist.

Methods: In a Sequential Parallel Comparison Design study, patients were pre-randomized to: a) 10 mg/d of CERC-501 for 6 days, b) 20 mg/d of CERC-501 for 6 days, c) placebo for 3 days followed by 10 mg/d of CERC- 501 for 3 days, d) placebo for 3 days followed by 20 mg/d of CERC-501 for 3 days, or e) placebo for 6 days.

Results: The study was terminated early by the National Institute of Mental Health due to slow enrollment (N = 8). The weighted mean difference of changes (drug vs placebo) in the 6-item Hamilton Depression Rating Scale (HAMD-6) (primary outcome measure) (1.28), Montgomery-Åsberg Depression Rating Scale (MADRS) (2.33), Perceived Stress Scale (1.01), Symptoms of Depression Questionnaire (9.17), Positive Affect Scale (PAS) (6.39), Symptom Questionnaire (SQ) Depression scale (2.94), SQ Anger- Hostility scale (1.67), and Patient-Reported Outcomes Measurement Information System Satisfaction with Participation in Discretionary Social Activities (4.67) scores were all numerically but not statistically greater for CERC-501 than for placebo.

Conclusions: Although the small sample size limits the ability to draw conclusions, results suggest that CERC-501 may have antidepressant effects. Additional studies are necessary to further explore these effects of CERC-501.
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http://dx.doi.org/10.12788/acp.0003DOI Listing
February 2020

Cerebrospinal fluid proteome evaluation in major depressive disorder by mass spectrometry.

BMC Psychiatry 2020 10 1;20(1):481. Epub 2020 Oct 1.

Basic Biomedical Science Department, University of South Dakota, 414 E Clark St, Vermillion, SD, 57069, USA.

Background: Depression affects approximately 7.1% of the United States population every year and has an annual economic burden of over $210 billion dollars. Several recent studies have sought to investigate the pathophysiology of depression utilizing focused cerebrospinal fluid (CSF) and serum analysis. Inflammation and metabolic dysfunction have emerged as potential etiological factors from these studies. A dysregulation in the levels of inflammatory proteins such as IL-12, TNF, IL-6 and IFN-γ have been found to be significantly correlated with depression.

Methods: CSF samples were obtained from 15 patients, seven with major depressive disorder and eight age- and gender-matched non-psychiatric controls. CSF protein profiles were obtained using quantitative mass spectrometry. The data were analyzed by Progenesis QI proteomics software to identify significantly dysregulated proteins. The results were subjected to bioinformatics analysis using the Ingenuity Pathway Analysis suite to obtain unbiased mechanistic insight into biologically relevant interactions and pathways.

Results: Several dysregulated proteins were identified. Bioinformatics analysis indicated that the potential disorder/disease pathways include inflammatory response, metabolic disease and organismal injury. Molecular and cellular functions that were affected include cellular compromise, cell-to-cell signaling & interaction, cellular movement, protein synthesis, and cellular development. The major canonical pathway that was upregulated was acute phase response signaling. Endogenous upstream regulators that may influence dysregulation of proinflammatory molecules associated with depression are interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), oncostatin M, PR domain zinc finger protein 1 (PRDM1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A).

Conclusions: The proteome profiling data in this report identifies several potential biological functions that may be involved in the pathophysiology of major depressive disorder. Future research into how the differential expression of these proteins is involved in the etiology and severity of depression will be important.
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http://dx.doi.org/10.1186/s12888-020-02874-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528485PMC
October 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

Peripheral vascular endothelial growth factor changes after transcranial magnetic stimulation in treatment-resistant depression.

Neuroreport 2020 11;31(16):1121-1127

Butler Hospital TMS Clinic and Neuromodulation Research Facility.

Objectives: To determine if vascular endothelial growth factor (VEGF) changes with transcranial magnetic stimulation (TMS) in treatment-resistant major depressive disorder (MDD).

Methods: Serum from a naturalistic population of 15 patients with MDD was collected at baseline and after standard TMS treatment. VEGF concentration was determined via ELISA. Inventory of Depressive Symptomatology Self Report and Patient Health Questionnaire were used as a measure of depression symptom severity, clinical response and remission. Mann-Whitney U and Kendall's Tau Correlation were used for continuous variables.

Results: VEGF increased from pre- to post-TMS (+30.3%) in remitters whereas VEGF decreased in non-remitters (-9.87%) (P < 0.05). This same pattern was observed when comparing mean %change in VEGF between responders (+14.7%) and non-responders (-14.9%) (P = 0.054). Correlation was present between change in VEGF concentration (baseline to post) and change in Inventory of Depressive Symptomatology-Self Report at Tx30 (r = -0.371, P < 0.054), reflecting greater increases in VEGF linked to greater improvement in depressive symptoms following the standard 6-week course of TMS.

Conclusion: Patients with a successful treatment with TMS had significantly greater increase in VEGF from baseline to after treatment compared to non-responders/non-remitters and a larger increase in VEGF was associated with greater improvement in depressive symptoms after TMS. This is the first report examining VEGF levels in depressed patients receiving TMS. This study provides correlative data supporting further investigation into VEGF's role as an important mediator in the processes underpinning TMS' antidepressant effects and as a potential biomarker of clinical outcomes.
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http://dx.doi.org/10.1097/WNR.0000000000001523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541741PMC
November 2020

Clinical outcomes in a large registry of patients with major depressive disorder treated with Transcranial Magnetic Stimulation.

J Affect Disord 2020 12 7;277:65-74. Epub 2020 Aug 7.

Nashville NeuroCare Therapy, Franklin, TN, USA.

Background: Randomized clinical trials have demonstrated that Transcranial Magnetic Stimulation (TMS) is an effective treatment for episodes of major depressive disorder (MDD). However, characterization of outcomes in routine clinical practice is needed, as well as identification of patient- and treatment-related outcome predictors. This study documented patient-rated (PHQ-9) and clinician-rated (CGI-S) clinical outcomes in the NeuroStar® Advanced Therapy System Clinical Outcomes Registry.

Methods: Registry data were collected at 103 practice sites. Of 7759 participants, 5010 patients were included in an intent-to-treat (ITT) sample, defined as a primary MDD diagnosis, age ≥ 18, and completion of the PHQ-9 before TMS and with at least one PHQ-9 assessment after baseline. Completers (N = 3,814) were responders or had received ≥ 20 sessions and had an end of acute treatment PHQ-9 assessment. CGI-S ratings were obtained in smaller samples.

Results: In the total ITT and Completer samples, response (58-83%) and remission (28-62%) rates were notably high across self-report and clinician-administered assessments. Female patients and those treated with a larger number of pulses per session had superior clinical outcomes.

Limitations: Site participation in the registry was voluntary and treatment was open label.

Conclusions: The extent of clinical benefit reported by patients and clinicians following TMS in routine practice compares favorably with alternative interventions for treatment-resistant depression. Strong efficacy and the low side effect and medical risk profile suggest that TMS be evaluated as a first-line treatment for MDD. The findings derive from the largest registry of clinical outcomes in MDD for any treatment.
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http://dx.doi.org/10.1016/j.jad.2020.08.005DOI Listing
December 2020

Do deviations from the 5 sessions per week schedule impact outcomes of transcranial magnetic stimulation for major depressive disorder?

Brain Stimul 2020 Nov - Dec;13(6):1491-1493. Epub 2020 Aug 6.

Butler Hospital TMS Clinic and Neuromodulation Research Facility, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111778PMC
August 2020

The Future Is Now? Rapid Advances by Brain Stimulation Innovation.

Am J Psychiatry 2020 08;177(8):654-656

Department of Psychiatry and Human Behavior, Brown University, Providence, R.I. (Carpenter, Philip); Butler Hospital TMS Clinic and Neuromodulation Research Facility, Providence (Carpenter); and Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence (Philip).

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http://dx.doi.org/10.1176/appi.ajp.2020.20060844DOI Listing
August 2020

Low-Dose Testosterone Augmentation for Antidepressant-Resistant Major Depressive Disorder in Women: An 8-Week Randomized Placebo-Controlled Study.

Am J Psychiatry 2020 10 14;177(10):965-973. Epub 2020 Jul 14.

Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (Dichtel, Kimball, Miller); Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston (Nyer, Mischoulon, Deckersbach, Dougherty, Yeung, Cassano, Hahn, Farabaugh, Pedrelli, Trinh, Dording, Cusin, Papakostas, Chang, Fisher, Shapero, Chen, Fava); Department of Psychiatry, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston (Brady); Biostatistics Center, Massachusetts General Hospital, Boston (Schoenfeld); Butler Hospital and Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Medicine, Brown University, Providence, R.I. (Carpenter, Tyrka, Price); Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston (Rao); Mayo Clinic Endocrine Laboratory, Rochester, Minn. (Singh).

Objective: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation.

Methods: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21-70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity.

Results: The participants' mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo.

Conclusions: Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.
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http://dx.doi.org/10.1176/appi.ajp.2020.19080844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748292PMC
October 2020

Mapping PTSD symptoms to brain networks: a machine learning study.

Transl Psychiatry 2020 06 18;10(1):195. Epub 2020 Jun 18.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA.

Posttraumatic Stress Disorder (PTSD) is a prevalent and debilitating condition with complex and variable presentation. While PTSD symptom domains (intrusion, avoidance, cognition/mood, and arousal/reactivity) correlate highly, the relative importance of these symptom subsets often differs across patients. In this study, we used machine learning to derive how PTSD symptom subsets differ based upon brain functional connectivity. We acquired resting-state magnetic resonance imaging in a sample (N = 50) of PTSD patients and characterized clinical features using the PTSD Checklist for DSM-5 (PCL-5). We compared connectivity among 100 cortical and subcortical regions within the default mode, salience, executive, and affective networks. We then used principal component analysis and least-angle regression (LARS) to identify relationships between symptom domain severity and brain networks. We found connectivity predicted PTSD symptom profiles. The goodness of fit (R) for total PCL-5 score was 0.29 and the R for intrusion, avoidance, cognition/mood, and arousal/reactivity symptoms was 0.33, 0.23, -0.01, and 0.06, respectively. The model performed significantly better than chance in predicting total PCL-5 score (p = 0.030) as well as intrusion and avoidance scores (p = 0.002 and p = 0.034). It was not able to predict cognition and arousal scores (p = 0.412 and p = 0.164). While this work requires replication, these findings demonstrate that this computational approach can directly link PTSD symptom domains with neural network connectivity patterns. This line of research provides an important step toward data-driven diagnostic assessments in PTSD, and the use of computational methods to identify individual patterns of network pathology that can be leveraged toward individualized treatment.
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http://dx.doi.org/10.1038/s41398-020-00879-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303205PMC
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

Transient aphasia induced by intermittent theta burst stimulation.

Brain Stimul 2020 Jul - Aug;13(4):941-942. Epub 2020 Mar 25.

VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, RI, 02908, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Butler Hospital, Providence, RI, USA.

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http://dx.doi.org/10.1016/j.brs.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343258PMC
March 2020

Molecular markers of neuroendocrine function and mitochondrial biogenesis associated with early life stress.

Psychoneuroendocrinology 2020 06 20;116:104632. Epub 2020 Feb 20.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA; Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA.

Objective: Glucocorticoid receptor gene (NR3C1) promoter methylation influences cellular expression of the glucocorticoid receptor and is a proposed mechanism by which early life stress impacts neuroendocrine function. Mitochondria are sensitive and responsive to neuroendocrine stress signaling through the glucocorticoid receptor, and recent evidence with this sample and others shows that mitochondrial DNA copy number (mtDNAcn) is increased in adults with a history of early stress. No prior work has examined the role of NR3C1 methylation in the association between early life stress and mtDNAcn alterations.

Methods: Adult participants (n = 290) completed diagnostic interviews and questionnaires characterizing early stress and lifetime psychiatric symptoms. Medical conditions, active substance abuse, and prescription medications other than oral contraceptives were exclusionary. Subjects with a history of lifetime bipolar, obsessive-compulsive, or psychotic disorders were excluded; individuals with other forms of major psychopathology were included. Whole blood mtDNAcn was measured using qPCR; NR3C1 methylation was measured via pyrosequencing. Multiple regression and bootstrapping procedures tested NR3C1 methylation as a mediator of effects of early stress on mtDNAcn.

Results: The positive association between early adversity and mtDNAcn (p = .02) was mediated by negative associations of early adversity with NR3C1 methylation (p = .02) and NR3C1 methylation with mtDNAcn (p < .001). The indirect effect involving early adversity, NR3C1 methylation, and mtDNAcn was significant (95 % CI [.002, .030]).

Conclusions: NR3C1 methylation significantly mediates the association between early stress and mtDNAcn, suggesting that glucocorticoid receptor signaling may be a mechanistic pathway underlying mtDNAcn alterations of interest for future longitudinal work.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887859PMC
June 2020

Psychedelics and Psychedelic-Assisted Psychotherapy.

Am J Psychiatry 2020 05 26;177(5):391-410. 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).

Objective: The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders.

Methods: Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on "psilocybin," "lysergic acid diethylamide," "LSD," "ayahuasca," "-methylenedioxymethamphetamine," and "MDMA," in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms "clinical trial," "therapy," or "imaging" in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), -methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care.

Results: The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as "breakthrough therapies" for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders.

Conclusions: Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.
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http://dx.doi.org/10.1176/appi.ajp.2019.19010035DOI Listing
May 2020

Safety of rTMS in patients with intracranial metallic objects.

Brain Stimul 2020 May - Jun;13(3):928-929. Epub 2019 Dec 28.

Neuromodulation Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2019.12.010DOI Listing
December 2019

Can early treatment response serve as a predictor of antidepressant outcome of repetitive Transcranial Magnetic Stimulation?

Brain Stimul 2020 Mar - Apr;13(2):420-421. Epub 2019 Dec 16.

Butler Hospital Neuromodulation Research Facility, 345 Blackstone Blvd, Providence, RI, USA; Department of Psychiatry and Human Behavior, Warren Alpert Medical School at Brown University, USA. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094132PMC
December 2019

Measurement of executive functioning with the National Institute of Health Toolbox and the association to anxiety/depressive symptomatology in childhood/adolescence.

Child Neuropsychol 2020 08 26;26(6):754-769. Epub 2019 Dec 26.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University , Providence, RI, USA.

Introduction: Despite preliminary research, there remain inconsistent findings with regard to the role of executive functioning (EF) deficits in childhood anxiety and depression. This report examined the association of The National Institute of Health (NIH) Toolbox to clinical neuropsychological measures and to childhood, anxiety/depressive symptomatology. Methods: One-hundred eight children and adolescents completed the three EF measures from the NIH Toolbox (List Sorting Working Memory Test [LSWMT], Dimensional Change Card Sorting Test [DCCST], and Flanker Test of Attention and Inhibition [Flanker]) in an outpatient neuropsychology program. These tests were compared to established measures of EF in terms of linear correlations and detection of impairment. Heaton's Global Deficit Score (GDS) was utilized to calculate impairment. The Toolbox-EF measures were paired with parent-reported EF symptoms (Behavior Rating Inventory of Executive Function [BRIEF2]) to identify the role of EF in childhood anxiety/depressive symptomatology.

Results: Toolbox-EF measures displayed medium sized correlations with their clinically comparable counterparts, and generally did not differ in their detection of impairment. Toolbox-GDS was associated with depression diagnosis and clinically significant child-reported anxiety and depressive symptoms. Together, Toolbox/BRIEF2 accounted for 26.8-30.9% of elevated depressive symptom variance, but only 13.2-14% of elevated anxiety symptom variance. Further, EF impairment was associated with depression across self report, parent report, and clinical diagnosis.

Discussion: The NIH Toolbox-EF measures display comparable psychometric properties to clinically available EF measures in a pediatric (primarily psychiatric) neuropsychology setting. The Toolbox appears to display an appropriate ability to detect EF deficits secondary to self-reported depression in childhood.
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http://dx.doi.org/10.1080/09297049.2019.1708295DOI Listing
August 2020
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