Seeking New Solutions Addressing Structural Racism, Childhood Trauma, Suicidal Behaviors Across Sexual Orientations, and Postpartum Depression

Since our September 2020 editorial (1) where we indicated that we would prioritize racism and inequities papers, we have placed 30 articles in the Antiracism Resources section of our homepage, a total that represents 11% of all that we published in the Journal over that time span. In that editorial we also made a commitment to further enhance inclusiveness and diversity in the Journal in relation to authorship and reviewers. We now can collect, on a voluntary basis, demographic information from anyone who is creating or updating their account within our submission and review system. This information is walled off from individual submission data, so while we cannot report on percentages of submissions authored or reviewed by specific populations, we can track over time whether our overall author and reviewer constituencies reflect appropriate representation. For our first reporting of these data, as of July 1, 2023, there were 2,125 individuals from whom we have demographic information to inform us about the representativeness of our contributors in terms of race (White 64.9%, Asian or Pacific Islander 20.4%, Hispanic or Latino/a/x 5.6%, Black 3.5%) and gender (male 48.2%, female 46.3%, nonbinary/gender diverse 1.8%). Our intent is to track this annually to gauge whether the diversity of our authors and reviewers is increasing, staying idle, or decreasing.

Additionally, in our September 2022 update (2) we indicated that we would make improvements in our processes to foster close examination of participant sociodemographic data reporting and the methods used to evaluate such data in the research papers published in the Journal. Briefly, this required that all papers report the sociodemographic data derived from the study of human participants, and that authors answer questions on how these data were ascertained. Reviewers and editors were encouraged to engage in a dialog with authors about the adequacy of these efforts. Since the participant data ascertainment questions became required late last year, there have been 15 instances in which the author’s original answers to the questions at submission have led to a change in the presentation of findings within the paper itself. We feel these changes not only improved the papers but served to improve the literature.

We begin the issue with an overview by Drs. Justin Russell, Sara Heyn, and Ryan Herringa from the University of Wisconsin–Madison (3) that focuses on developmental factors relevant to the putative neural mechanisms underlying childhood PTSD with implications for novel treatment strategies for traumatized youth. This overview is followed by a review addressing the impact of structural racism on the development of research careers in psychiatry. Dr. Alik Widge from the University of Minnesota, along with members of the American Psychiatric Association Council on Research (4), examine the factors related to structural racism that have impeded individuals from minoritized populations from developing successful psychiatric research careers and provide potential pathways to overcome these barriers with the goal of enhancing diversity among psychiatric researchers.

Due to societal factors, including prejudices and discrimination, individuals identifying as belonging to a sexual minority face considerable long-term stressors related to their sexual orientation that are not experienced by heterosexual individuals. Chum and colleagues (5) attempt to further understand the extreme impact of these stressors on individuals belonging to sexual minorities by focusing on rates of engaging in suicide-related behavior (nonfatal and fatal self-harm) across heterosexual, gay/lesbian, and bisexual individuals. To accomplish this, the researchers used survey and medical record data collected longitudinally from 123,995 randomly chosen individuals in Ontario, Canada. The average follow-up time for participants was 11.4 years and, in this sample, there were 3,192 individuals that engaged in at least one act of suicide-related behavior, and 164 individuals who died by suicide. As expected, the rates of suicide-related behavior were increased in individuals that self-identified as belonging to a sexual minority. For example, the rate of suicide-related behaviors in heterosexual individuals was 224.7 per 100,000 person years compared with 664.7 per 100,000 person years for gay/lesbian individuals and 5911.9 per 100,000 person years for bisexual individuals. When taking age and gender into account and comparing with heterosexual individuals, the researchers found that the risk to engage in suicidal-related behavior increased 2.1-fold for gay/lesbian individuals and 3-fold for bisexual individuals. In his editorial (6), Dr. Gregory Simon from the Kaiser Permanente Washington Health Research Institute discusses how these findings fit in with previous studies and the methodological improvements that were used in this study. He also emphasizes the stresses faced by individuals belonging to sexual minorities and the need for clinicians to account for the increased risks that these individuals face.

Prior studies have demonstrated the efficacy of the neurosteroid allopregnanolone (brexanolone), administered intravenously, for the treatment of postpartum depression, which in 2019 was approved by the FDA for that indication. Allopregnanolone is a naturally occurring metabolite of progesterone, and its antidepressant action is thought to be mediated by its effects as a positive allosteric GABA_A receptor modulator. Allopregnanolone plasma levels decrease after giving birth and some studies suggest that postpartum depression is associated with changes in allopregnanolone levels. Zuranolone is a synthetic orally active neurosteroid that, like allopregnanolone, also acts as a positive allosteric GABA_A receptor modulator at synaptic and extra-synaptic sites. Prior studies have demonstrated rapid efficacy of zuranolone, 30 mg/day, for treating postpartum depression. Deligiannidis and colleagues (7) aimed to characterize the safety and efficacy of a higher dose of zuranolone, 50 mg/day, in women with postpartum depression. In this double-blind placebo-controlled study, 98 women with postpartum depression received zuranolone, 50 mg/day, for 2 weeks, and an additional 98 women with postpartum depression received placebo. Of the participants, 38.3% identified as Hispanic/Latina and 21.9% as Black/African American. The primary outcome measure was change from baseline to day 15 on the Hamilton Rating Scale for Depression (HAM/D-17). Participants were excluded if they had a history of bipolar disorder, and they could remain on antidepressant medication if they had been taking them for 30 days or more prior to study entry. Results demonstrated that compared with the placebo group, the zuranolone group had significantly greater reductions in depressive symptoms assessed on day 15 as well as on days 3, 28, and 45. At day 14 a nonsignificant effect on remission was found such that 26.9% of patients treated with zuranolone had remitted as compared with 16.7% in the placebo group. At day 45, a significant effect was observed with 44% of the zuranolone patients in remission compared to 29.4% in the placebo group. The patients in this study also had significant levels of anxiety and at days 3, 8, 15, and 45 the zuranolone group demonstrated significantly greater reductions in anxiety compared with the placebo group. The most common adverse events associated with zuranolone administration were somnolence, dizziness, and sedation, and due to adverse events, 16 patients in the zuranolone group required dose reductions.

Similar to the aforementioned study, Clayton and colleagues (8) present data from a randomized double-blind clinical trial comparing the effects of zuranolone, 50 mg/day, versus placebo, this time in patients with major depression. The intervention (drug or placebo) was administered for 14 days, and patients with major depression were followed for 45 days. The primary outcome measure in this study was the change in the HAMD-17 score from baseline to 15 days. Participants could remain on their antidepressant medication if they had been on it for at least 2 months, and individuals with treatment-resistant depression were excluded. The analysis used data from 266 participants in the zuranolone group and 268 in the placebo group, demonstrating a significantly greater reduction in HAMD-17 scores at 15 days in the zuranolone compared with the placebo group. Significant effects were also detected at the 3-day assessment and at the other assessment points continuing until 42 days as the study was ending. As in the zuranolone postpartum depression study, in this study zuranolone was also found to have anti-anxiety effects. While zuranolone was superior to placebo as assessed by changes in the HAMD-17 scores, remission rates between the zuranolone and placebo groups were significantly different only on day 3 and not on the other assessment days. The most common side effects associated with zuranolone were somnolence (15.3%), dizziness (13.8%), headache (10.8%), sedation (7.5%), and diarrhea (3.0%), and 8.6% of the patients in the zuranolone group had their dose reduced because of adverse events. Dr. Daniel Pine from NIMH contributes an editorial discussing both zuranolone studies, highlighting the novel therapeutic strategy of using neurosteroids for the treatment of depression as well as the pathway of drug discovery for these compounds from translational neuroscience studies to the clinic (9).

Several copy number variants (CNVs)—the duplication or deletion of sequences of the genome—have been associated with neuropsychiatric illnesses. For example, individuals with the 22q11.2 deletion are at a marked risk of developing schizophrenia-like symptoms and may also develop autism-like traits. Recent work has demonstrated the value of studying individuals with these genetic risk variants to understand how specific genetic alterations lead to alterations in brain function that underlie psychiatric illness-related symptoms. Additionally, as in the 22q11.2 example, it is well established that a given risk CNV can demonstrate pleiotropy resulting in symptoms related to different illnesses. To better understand the relations among relevant CNVs, brain structural alterations, and neuropsychiatric illnesses, Kumar and colleagues (10) present data from a subset of individuals in the ENIGMA sample focusing on 11 depletion or duplication CNVs. The sample consisted of 675 individuals with CNVs and 782 control individuals from which structural MRI data (i.e., subcortical volume, thickness, and surface area) were analyzed, as well as other data from the ENIGMA sample for individuals with autism spectrum disorder, schizophrenia, ADHD, OCD, bipolar disorder, and major depression. The seven subcortical regions studied included the nucleus accumbens, amygdala, caudate, hippocampus, putamen, pallidum, and thalamus. Findings demonstrated that six CNVs were associated with altered intracranial volume, all the CNVs were associated with one or more subcortical structural measure, nine CNVs were significantly associated with subcortical volumes, and five were associated with structural measures of the amygdala and hippocampus. Individuals with 22q11.2 deletions showed the greatest subcortical changes and in general those CNVs associated with higher risks for illness had greater subcortical alterations. Related to the pleiotropy and diagnostic overlap associated with the CNVs, the researchers found that the different CNVs had both shared and distinct patterns of subcortical alterations, and some common effects were identified between the CNVs and the psychiatric illnesses noted above. In their editorial (11), Drs. Konrad Wagstyl from University College London and Armin Raznahan from NIMH describe the findings in detail and discuss the potential longer-term clinical relevance of a “genetics first” approach linking genes to pathways and pathways to symptoms and ultimately to new treatments.

In addition to providing an update on our DEIBA efforts, this issue of the Journal contains papers that address a range of significant topics. Importantly, we include papers that characterize the impacts of structural racism on the psychiatric research work force as well as the substantial effects of societal biases against sexual and gender minorities on suicidal behavior. Other papers in this issue cover topics related to PTSD in youth, assessing the antidepressant efficacy of zuranolone, and associations between genetic variation and alterations in brain structure that are linked to psychopathology. Among the major findings from these studies: 1) individuals from minoritized populations are markedly underrepresented in psychiatry in general, and more specifically in academic psychiatry, as a result of the long-term consequences of structural racism; 2) gay/lesbian and bisexual individuals have a 2–3 times increased risk to engage in suicide-related self-harm behaviors; 3) the characteristics of PTSD in youth as well as developmental insights into PTSD-related neural circuit alterations involving fear processing, emotion-related memory, and fear extinction; 4) copy number genetic variants associated with neurodevelopmental disorders have some distinct and some shared patterns of subcortical brain alterations that are associated with psychiatric symptoms; and 5) zuranolone, a drug that positively modulates GABA_A receptor function, appears to have rapid antidepressant effects that significantly differ from placebo.