COVID-19, Substance Use, Anorexia Nervosa, 22q11.2 Deletion Syndrome, and Stress

In addition to the direct effects of the COVID-19 virus on morbidity and mortality, the acute and chronic psychological stress affecting the world population is unprecedented. Understandably, we are already observing marked increases in fear, anxiety, and grieving responses in our patients as well as in those who were previously not affected. Although many of these responses are expected and in some cases adaptive, they have the potential to worsen existing conditions and, for those previously unaffected, to morph into psychopathology. There is no question that over the long term, well beyond the pandemic, the COVID-19 experience will result in an increase in, and exacerbation of, mental illness. It is vitally important that we understand the current effects of the pandemic on psychological distress and anticipate the future mental health needs of the general population. In this issue, we have a commentary by Zhou et al. (1), from West China Hospital in Chengdu, that reports on the impact of the COVID-19 pandemic on psychiatric and neurological patients. The authors detail a worsening of psychiatric symptoms and difficulties with access to services and medications for many of the patients treated in their clinics. Proposed strategies to address the access and medication problems caused by the pandemic are discussed, providing lessons from which we can all learn. One innovative idea involves developing new services for the free home delivery of medications to patients.

Three letters to the editor address other important COVID-19 issues. From Wuhan, China, Lin et al. (2) bring our attention to the psychological burden of health care providers by demonstrating that, although many health care workers have experienced significant anxiety, depression, and insomnia, only a relatively small proportion received help to deal with their distress. Jenny Boyer then alerts us to the vulnerabilities of patients with substance use concerns in relation to COVID-19 and its treatment (3). In the third COVID-related letter, Kalin et al. (4) report on the successful use of telehealth strategies for treating psychiatric inpatients, an innovative approach that maintains a high quality of care while reinforcing social distancing and conserving personal protective equipment.

For those of you who are interested in the historical underpinnings of how we currently conceptualize factors contributing to the development of psychopathology, Ken Kendler contributes a review of the early theories involving the influences of stress (5). Focusing on the 19th century, Kendler reminds us that the importance of stress in psychiatric thinking is not new, and he reviews early ideas about stress in relation to preexisting predisposing factors and more concurrent “exciting” stress-related factors. It is fascinating to see how these early theoretical underpinnings have evolved into our current thinking and how recent empirical research, including efforts using molecular methods and neuroimaging, has provided mechanisms by which the interactions between predisposing tendencies and current stressors are mediated. This topic could not be more relevant given our current struggles with the ongoing and consuming stress of COVID-19, especially as, from a psychiatric perspective, we think about who will be most affected. At a scientific level, this speaks to the need to understand factors underlying individual differences in vulnerability and resilience as a means to develop better strategies to prevent the development of stress-related psychopathology.

Schizophrenia is one of the most heritable psychiatric disorders. Although through genome-wide association studies we are making progress in understanding its complex genetics, how specific genetic alterations are related to the pathophysiology of schizophrenia remains unclear. Therein lies the value of studying patients who present with schizophrenia or schizophrenia-like symptoms who have known and well-characterized rare genetic variants. Using neuroimaging to study a large sample (N=533) of individuals with 22q11DS, also known as velocardiofacial syndrome, Ching and colleagues (6) report overlaps between subcortical structural brain alterations associated with this syndrome and those of other psychiatric disorders. 22q11DS, caused by a microdeletion on chromosome 22, is commonly associated with the development of schizophrenia and, in this regard, provides insights into potential genetic underpinnings of schizophrenia and possibly other psychiatric illnesses. The investigators found greater reductions in volumes of the thalamus, hippocampus, and amygdala in subjects with 22q11DS who developed psychosis compared with those who did not develop psychosis. By analyzing the shape of structures, the investigators also found a relation between the size of the microdeletion, or genetic defect, and the magnitude of subregional alterations in the hippocampus, thalamus, and other structures. In their editorial, Drs. Dan Eisenberg, Michael Gregory, and Karen Berman from the Clinical and Translational Neuroscience Branch at the National Institute of Mental Health (7) emphasize the importance and value of studying rare genetic syndromes that are associated with psychiatric illnesses. In addition to reviewing the findings, this editorial provides guidance in how to think about, and study, patients with known genetic defects who are phenotypically similar to those with a specific psychiatric disorder.

Anorexia nervosa is a debilitating disorder that at its core affects one of our most essential motivational states and its associated behaviors, that is, eating. When severe, the symptoms of this illness are frequently life threatening. Research like that presented in this issue by Kaye et al. (8) is critical, as a deeper understanding of brain alterations associated with anorexia nervosa provides a basis for new treatment development. In their article, Kaye et al. present data in which they demonstrate that even when in a remitted state, patients with anorexia nervosa have alterations in brain regions involved with linking sensory signals to reward value and subsequent motivated behaviors. This carefully performed study assessed neural response to taste after subjects had just eaten, in comparison with a period of fasting. When comparing responses between the hungry and fed conditions, control subjects displayed increased activation of the ventral caudal putamen, whereas remitted anorexia nervosa subjects displayed the opposite effect, reduced activation during hunger. This region is part of the reward circuitry and via its inputs and outputs is in a position to link the reinforcing value of food to eating behavior. Other alterations in the insula were observed in subjects with anorexia nervosa, including reduced functional connectivity between the insula and ventral caudal putamen during conditions of hunger. The insula is a key cortical region involved with the processing of internal physiological signals, and its linkages to the striatum provide a pathway by which these signals can be used to influence the expression of motivated behavior. Drs. Javaras and Pizzagalli from McLean Hospital and Harvard Medical School provide an editorial in which they discuss this work in relation to the seriousness of the illness and the importance of developing more effective treatment strategies (9). They also comment on the need to understand whether reward-related deficits in anorexia nervosa are limited to food-related cues or are more general in relation to various types of rewards.

Cannabis is widely used by the U.S. population and has been legalized for recreational or medical uses in many states. Two articles in this issue focus on cannabis: one reporting on the use of cannabis in individuals experiencing pain, and the other presenting data linking the use of cannabis to violent behavior. Using two large databases, one collected between 2001 and 2002 and the other collected between 2012 and 2013, Hasin et al. (10) assessed the relation between experiencing physical pain and cannabis use. In both samples, the prevalence of pain in adults was estimated to be around 20%. The findings demonstrated an increase in nonmedical cannabis use in individuals experiencing pain compared with those who were pain free, as well as a significantly greater incidence of cannabis use disorder in those with pain. In addition, the data from 2012–2013 relative to the data from 2001–2002 suggest an increase over time in the frequent use of cannabis in individuals reporting pain.

In the second article, Dellazizzo and coauthors (11) perform a meta-analysis to assess, in adolescents and young adults, the relation between cannabis use and the likelihood of perpetrating physical violence. Overall, the findings demonstrate a 2.1 odds ratio for the relation between cannabis use and committing violent behavior. Additionally, the authors found that the odds ratio increased to 2.8 for heavy cannabis users. The authors note that in youths, cannabis is a moderate risk factor for perpetrating violence, and the authors emphasize the potential importance of this finding in relation to the high prevalence of cannabis use.

Dr. Kathleen T. Brady, from the Medical University of South Carolina and a deputy editor of the Journal, contributes an editorial on the Hasin et al. article focused on cannabis and pain that is also relevant to the Dellazizzo et al. article linking cannabis use to violence. In her editorial (12), she emphasizes the clinical relevance of the relation between cannabis use disorder and pain. She acknowledges the role that cannabinoids can have in alleviating pain but also cautions about their misuse, drawing parallels to how initial pain management efforts contributed to the opioid epidemic. An important message in her editorial relates to the medical use of cannabis and its legalization for recreational purposes. Here, she strongly argues for established Food and Drug Administration processes to be used for the approval of, and the development of guidelines for, the medical use of cannabinoids.

According to the National Institute on Alcohol Abuse and Alcoholism, an estimated 15 million people in the United States struggle with alcohol use disorder (13). In addition to the acute effects of alcohol, including clouding judgment and acting as a depressant, alcohol use disorder is highly comorbid with psychiatric illnesses, thereby adding to their morbidity and mortality. To assess the extent to which alcohol use disorder is a risk factor for suicide, Edwards and colleagues (14) examined data from Swedish population registries constituting more than 2.2 million individuals born between 1950 and 1970. Not surprisingly, the findings revealed a marked increase in the lifetime rate of suicides associated with alcohol use disorder. In addition, these effects appeared to be greater in women, which could in part be attributed to the confounding factors of psychiatric comorbidities. Importantly, in an analysis that excluded patients with alcohol use disorder with psychiatric comorbidities, the relation between alcohol use disorder and suicide remained considerable. In both men and women, the relation between alcohol use disorder and suicide was greater when assessed closer in time to the initial registry of the alcohol use problem and when the onset of alcohol use disorder occurred at an earlier age. The authors also performed an analysis suggesting a complex role of familial influences in the association between alcohol use disorder and suicide. Dr. Deborah Hasin, from Columbia University, writes an editorial that emphasizes the importance of alcohol in suicide, places this finding in the context of other work, and addresses methodological issues. In her editorial (15), she asks the important question regarding the extent to which the relation between alcohol and suicide documented in Sweden may generalize to, or be even worse in, countries with considerably less social and medical support.