2021 Articles of Import and Impact

Ned H. Kalin, M.D., Editor-in-Chief

One of the most important and relevant articles that we published this year in the Journal is a call to action for psychiatry to confront and change the structural racism framework that significantly contributes to mental health care inequities (1). Dr. Ruth Shim from the University of California at Davis begins by reviewing the concepts of race, structural racism, health care inequities, disparities, and social injustice. She draws attention to the different meanings of the terms “disparities” and “inequities” as they relate to health care delivery. By doing so, she advocates for the preferential use of the term inequities, as “inequities” links disparities in the delivery of care to the unjust policies and discrimination that drive these inequities. She also explicitly discusses the history of racism in psychiatry and describes how contemporary structural racism policies (e.g., residential segregation, the war on drugs) affect the social determinants of health that result in our present-day inequities in the delivery of and access to mental health care. This discussion is linked to recommendations aimed at how to take action toward dismantling structural racism in psychiatry and toward policies that facilitate equitable care. She asserts that change must begin at the personal level with the acceptance of one’s unintended biases and their consequences as well as education and self-reflection. She further emphasizes that it is critical for psychiatrists and mental health workers to make a commitment not only to advocate for mental health equity but to translate this advocacy into real action that will enable positive change. Importantly, efforts need to be targeted at the societal level to influence current leaders—or elect new leaders—who are committed to undoing and changing the public policies that underpin inequities in health care. As we avowed earlier in the Journal (2), the Deputy Editors and I have made the commitment to use the American Journal of Psychiatry as a means to combat structural racism and health care inequities. We are specifically focused on improving mental health care for individuals of color and more broadly for individuals from underprivileged and discriminated communities. We thank Dr. Shim for moving us forward in this direction, as we enthusiastically continue in our pursuit of this critical goal.

Elisabeth Binder, M.D., Ph.D., Deputy Editor

Costi et al. (3) report on a randomized placebo-controlled trial testing the effect of the potassium channel modulator ezogabine on dopamine circuit activity and clinical outcomes in patients with depression. This study is the culmination of a series of articles that have built the case for potassium channel KCNQ2/3 activators as potential antidepressant drugs. Initially molecular analyses in regions of the mesolimbic dopamine system in an animal model of chronic social stress discovered KCNQ2/3 to be among the most strongly upregulated transcripts in dopaminergic neurons in resilient animals (4). Indeed, increasing the activity of the channel in these neurons prevented negative behavioral outcomes of this stressor (5). Given the relevance of the mesolimbic dopamine system and the reward circuitry in core symptoms of depression, such as anhedonia, it was hypothesized that activation of these channels could contribute to antidepressant effects by eliciting functional changes in the brain reward system.

In 2011, the U.S. Food and Drug Administration (FDA) had approved ezogabine, a KCNQ2/3 activator as an anticonvulsant drug. Using a drug repurposing approach, oral administration in the animal model (5) as well as an open-label trial (6) of ezogabine in patients with major depression indicated effects both on depression symptoms as well as reward circuit activity. Costi et al. followed up on this hypothesis in a randomized controlled trial of ezogabine in depression, having changes in the reward circuit as the primary outcome, and changes in depression symptoms, including anhedonia, as secondary outcomes. While the brain imaging analyses only showed a nonsignificant change with the active drug, significant and clinically relevant reductions in overall depression symptoms as well as anhedonia were observed. Even though the negative results for the brain imaging biomarker indicate the complexities that such translational studies face, and further replications are needed, in my view, this is an important example of how findings from basic animal models related to transdiagnostic domains such as reward processing and stress can identify promising novel drug targets in psychiatry.

Kathleen T. Brady, M.D., Ph.D., Deputy Editor

Polysubstance use in individuals with substance use disorders is the rule rather than the exception to the rule. Specifically, 20%−25% of individuals who smoke cigarettes are heavy drinkers, and 60%−75% of individuals in treatment for alcohol use disorder smoke cigarettes. While we have FDA-approved treatments for alcohol use disorder as well as smoking cessation, it is estimated that less than 30% of individuals who meet criteria for alcohol use disorder receive these treatments (7). In many other areas of psychiatry, the use of more than one medication, particularly in treatment-resistant cases, is commonplace, but in the treatment of substance use disorders, this is not considered often enough. The study by Ray et al. (8) is exemplary in exploring strategies to treat an extremely common comorbidity, and in using combination therapy for treatment. Although the results were not overwhelmingly positive, the article provides some valuable information for clinicians about subpopulations of heavy drinkers/smokers who might benefit from combination therapy and reinforces the efficacy of varenicline in smoking cessation, even in heavy drinkers.

David A. Lewis, M.D., Deputy Editor

“Do no harm,” a critical dictum in the practice of medicine, is challenging to follow when effective treatments are accompanied by adverse effects. The challenge is compounded when the management of certain adverse effects can exacerbate others. In the treatment of schizophrenia, the use of antipsychotic medications can be highly effective in suppressing psychotic symptoms and improving quality of life. Yet these medications can also worsen the cognitive impairments attributable to the disease itself, due to their blockade of cholinergic receptors. Furthermore, this effect is frequently compounded by the use of additional anticholinergic medications, prescribed to mitigate other adverse effects of antipsychotic medications or to treat other clinical features of schizophrenia. The negative cognitive impact of the combined anticholinergic burden is clearly documented in the study by Joshi et al. (9). In a secondary data analysis of a large sample of individuals with a long-standing diagnosis of schizophrenia, they demonstrated a strong inverse relationship between anticholinergic burden and cognitive performance. In addition, the effect of anticholinergic burden was comparable across all domains of cognition assessed. Importantly, antipsychotic medications contributed more than half of the anticholinergic burden, suggesting that reducing adverse cognitive effects requires both the judicious dosing of antipsychotics and, when possible, the deprescription of other psychotropic drugs, especially when their original indication is no longer present. The authors thoughtfully acknowledge the limitations of their study, including the fact that the study design precludes a cause-effect determination between anticholinergic burden and cognitive impairments. Nevertheless, their conclusions are informative and sound in the light of other supporting evidence, and their recommendations for strategies to quantify and reduce anticholinergic burden should be considered by all physicians who care for people with schizophrenia.

Daniel S. Pine, M.D., Deputy Editor

Recent brain imaging research raises questions concerning clinical relevance. Failures to consistently detect large effect sizes suggests the need for considerable additional work. This is particularly important in children, given late maturation of many brain functions. Norman and colleagues (10) provide important new data from an imaging study of attention deficit hyperactivity disorder (ADHD) that moves the field one step closer to clinical relevance. The authors studied more than 250 children and adolescents, 110 of whom had clinically significant ADHD symptoms, for as long as 8 years with repeated clinical and brain imaging measures. They used measures of brain function derived from resting-state functional MRI, a technique that is scalable to large samples. The study provides benchmarks for other such efforts, in that the authors acquired considerable data in a well-characterized and carefully followed sample. Moreover, findings on the strength of relations between brain function and clinical profiles resembled results in other research: these relations were not large. Finally, the study demonstrated developmental relations among ADHD symptoms, treatment response, and brain function. Differences in brain function observed over time between healthy youths and patients with ADHD symptoms were largest in one subset of patients. This comprised the subgroup who manifested a relatively poor response to treatment. Thus, findings from Norman et al. use a longitudinal design to suggest how brain imaging research in children may become clinically relevant. This may occur by focusing studies on examinations of relations between brain function and treatment response.

Carolyn Rodriguez, M.D., Ph.D., Deputy Editor

Compulsive behaviors impair quality of life and functioning in individuals with obsessive-compulsive disorder (OCD) and related disorders. These maladaptive behaviors have been strongly linked to abnormal activity in the orbitofrontal cortex, as well as more general dysfunction in fronto-striatal circuits. The well-designed study by Price et al. (11) captured my attention for three reasons. First, it employs a rigorous mechanistic clinical approach using neuromodulation to increase and decrease orbitofrontal cortex activation to test whether it is a driver or overrider of compulsive behaviors. Second, the experimental modulation with cortical theta-burst stimulation occurs within the behavioral context of habit override training. Third, the study includes measurement of impact on acute neuroimaging indices and on laboratory markers of compulsive behavior vulnerability both acutely and at 1-week follow-up. Price and colleagues randomized participants with compulsive behavior disorders to either a single session of intermittent theta-burst stimulation (iTBS)—expected to increase OFC activity—or continuous TBS (cTBS)—expected to decrease activity. In each case, the neuromodulation was paired with a computer task providing practice in overriding an overlearned shock avoidance behavior. Functional MRI assessments were administered at pre- and post-neuromodulation. The authors reported that cTBS, more so than iTBS, had a beneficial effect on compulsive behaviors 90 minutes after the neuromodulation, and these effects persisted 1 week after cTBS. Additionally, neuroimaging findings confirmed target engagement and helped reveal both focal and neural network-level impacts of neuromodulation paired with behavioral training. This study opens promising new avenues for mechanistic and synergistic intervention development.

Madhukar H. Trivedi, M.D., Deputy Editor

Despite the recognition that exposure to traumatic events during childhood can dramatically alter developmental trajectory of neurobiological development, exactly how adversity affects brain development remains a question. Does adversity lead to faster or delayed brain development? Does the type of adversity matter? And are there specific circuits differentially affected by the type, severity, and duration of adversity? Understanding differential brain aging may provide understanding of mechanisms and targets for intervention. The study by Keding and colleagues (12) provides some answers to these questions. The study examined 234 girls, ages 8–18 years, and compared girls who were “typically developing” (i.e., no abuse or internalizing diagnosis; N=99), “resilient” (i.e., abuse, but no internalizing diagnosis; N=50), or “susceptible” (i.e., abuse and internalizing diagnosis; N=85) to predict brain age using gray matter volume in the whole brain and in emotion and language circuits. The study found that abuse was associated with reduced brain age—or delayed maturation—in emotion circuits, independent of whether there was an internalizing diagnosis. Neglect was associated with increased brain age—or advanced maturity—in whole brain, which suggests that different types of adversity and stress differentially impact brain development. Further, among girls who were abused, several regions were identified that contribute to emotion circuitry maturation differently among resilient versus susceptible girls. The report also moves beyond just looking at accelerated brain aging (i.e., neuroimaging-predicted brain age is higher than chronological age) and conceptualizes brain age lower than chronological age as delayed maturation. This is relevant to youths but whether it applies to individuals across the lifespan needs to be studied. These findings are very exciting, as they provide new insight into brain age specific to emotion and language circuits, which could possibly point to potential mechanistic differences related to how internalizing disorders may impact brain maturity. These results are promising and may lead to treatment strategies targeting specific circuits in the brain that are associated with adversity and stress.

Austin Blum, J.D., M.D., Editor-in-Chief

The American Journal of Psychiatry Residents’ Journal (AJP-RJ), currently in its 17th volume, continues its mission to advance the scholarship and creative work of residents, fellows, and medical students from the United States and Canada. Despite the ongoing challenges presented by the COVID-19 pandemic, AJP-RJ has thrived. Its quarterly issues have a broad geographic reach, the 2021–2022 editorial board attracted a record number of applicants, and AJP-RJ’s podcasts and social media presence have engaged a growing number of listeners and viewers. Of the numerous manuscripts published in AJP-RJ over the past year, I would like to highlight “Adrafinil: Psychostimulant and Purported Nootropic?” by Dr. Danielle Lowe and colleagues (13). Adrafinil has not been approved by the FDA; therefore, this agent (a prodrug of modafinil) is not well known to many American psychiatrists. Some individuals use it nonmedically as a cognitive enhancer, or “smart drug.” In their article, Lowe et al. review the limited clinical evidence for the use of adrafinil and summarize online “experience reports” (N=49) detailing individuals’ subjective accounts of adrafinil use. This work should remind psychiatrists to screen for the use of adrafinil or other supplements during the clinical encounter, especially in patients with a history of substance abuse. Finally, for readers who may be searching for their next podcast, I highly recommend “Hip-Hop Psychiatry” with Dr. Akeem Sule (interviewed by Blake Novy, M.D.). It is timely, empathetic, and sincere—the precise qualities to which AJP-RJ aspires.