DOI: 10.31038/EDMJ.2020441

Abstract

Objectives: Type 2 diabetes is the seventh leading cause of death and disability worldwide. Estimates suggest that by 2035, 642 million people worldwide will suffer from diabetes. Higher awareness of risks of type 2 diabetes is a prerequisite to prevent or delay the onset of diabetes but, little attention has been paid to identifying effective communication messages to raise public awareness of risks of this disease and this is the focus of this study.

Methods: A conjoint based procedure facilitated an experimental design testing the power of narrative persuasion messages as driving awareness of risks of type 2 diabetes based on stability of utilities. The sample comprised 50 Americans recruited by Luc.id, Inc.

Results: Similarity in response patterns to messages uncovered three mindsets, each responsive to different messages. We identified effective messages for each mindset and developed a prediction tool assigning a person/group in the population to a sample mindset.

Discussion: Members of Mindset1 respond to empowering messages depicting members as having control, as able to modify their behaviors. Members of Mindset2 respond to messages presenting doctors as enhancing the health literacy of members and informing them of ways to prevent diabetes. Members of Mindset3 respond to messages presenting patients as a resource for learning, information, and support. Messages used in campaigns emerged as ineffective across mindsets

Conclusion: The prediction tool assigning people to mindsets may enable professionals to detect the psychological mind-set of an individual and drive health behavior changes using effective messaging.

Keywords

Awareness, Communication, Diabetes, Narrative-Messaging, Public, Mindsets

Type 2 diabetes is a major cause of increasing mortality incurring vast expenditures. Direct costs of type 2 diabetes account for $1.31 trillion and additional indirect costs account for 35% of the total burden [1]. Type 2 diabetes is one of five leading causes of premature death in high-income countries [2]. In 2017, around 415 million adults suffered from Type 2 diabetes [2]. Estimates suggest that over the next decade, 642 million adults will suffer from type 2 diabetes [2]. Moreover, type 2 diabetes, thus far diagnosed among adults, is now expanding to adolescents and children, making it THE epidemic of the 21^st century [3]. So far, all interventions to maintain Glycemic control achieved sub-optimal outcomes [3-7]. Lack of Glycemic control leads to progress of type 2 diabetes resulting in a range of health complications, morbidity and disability [2].

Tremendous efforts to halt the expansion of type 2 diabetes involved: behavior-modification programs, pharmacological interventions and educational interventions. Whereas policy makers viewed these efforts as promising means to affect modifiable determinants of type 2 diabetes (i.e., obesity, sedentary lifestyles, smoking, stress), research evidence remains inconsistent [6-8]. Moreover, most interventions failed as program-compliance challenged patients and due to the global shortage in clinicians which limited program accessibility [9-14]. Research on pharmacological interventions suggests that lifestyle modifications, are, in fact, more efficacious [15]. No findings of other specific pharmacological interventions were published in papers. Last, research on educational interventions demonstrated contradictory results exposing provision barriers which inhibited intervention deployment [16,17]. In sum, to date, hypotheses of evaluation studies for interventions for control, prevention, and delay of the onset of type 2 diabetes, have not been corroborated. The prevalence of diabetes and the per capita expenditures of diabetes (direct and indirect costs) are rising and while they may be grounds for diabetes prevention, the awareness level among prediabetes and the rate of preventing interventions are low and of great concern [18].

Two recent studies that tested awareness among high risk British adults and among Americans, reported that half of participants demonstrated gaps in awareness of risks, symptoms and related behaviors [19,20]. Researchers recently acknowledged that individual-level prevention approaches are inadequate and thus unable to reverse epidemic trends, costly, and not scalable for targeting the healthy population [21]. Since lack of public information is a major barrier to risk awareness, researchers suggest the importance of increasing vigilance in reducing risks of type 2 diabetes by addressing gaps in public awareness [2,3,15,19,22,23].

Numerous institutions, including the World Health Organization, have recommended mass communication messaging to improve public awareness [22]. Studies in medicine, public health, and health communication, however, targeted patients rather than the healthy population [20-22]. Creating public awareness of the healthy population was thus far seen as less important than improving practices of patients [22]. The few studies that tested communication messaging for public awareness regarding general health issues, featured linkages among awareness behavior and health outcomes [23,24]. While research on communication messaging in general health topics is growing, the topic of communication messaging to the healthy population in type 2 diabetes, is unexplored [21,23-25].

One study presented a successful communication messaging campaign on determinants of type 2 diabetes but its reach was limited as it only engaged youth [21]. Another study on communication messaging in type 2 diabetes revealed that awareness of risks increased in the one Indian city where it was conducted [26]. Whereas studies on communication messaging in type 2 diabetes are scarce, findings of these two studies suggest that public campaigns may effectively raise awareness among many different segments of the healthy population and may reverse current concerning paths of behavioral trends in modifiable drivers of type 2 diabetes [21]. Since all groups in the population suffer from the burden of type 2 diabetes, this epidemic should be addressed, as other healthy issues, by effective communication messaging. An alternative as yet unexplored way to respond to previous calls to reduce risks of type 2 diabetes is to test and optimize messaging among healthy people. A systematic examination of effective campaigns indicates that in health disparities narrative messages have a persuasive impact on attitude change and behavioral modifications [27,28]. Also, facets that draw on the narrative persuasion theory, have been reported to bring individuals in the population to accept greater responsibility for their health [28]. In this study we draw on the theory of narrative persuasion in the daily life experiences of healthy people touching on risk awareness of Type 2 diabetes.

The Theoretical Framework and Hypotheses Development

A narrative comprises cohesive and coherent statements that may make up a story with an identifiable beginning, middle, and end and provide information about a daily phenomenon [29]. Narratives entail an integration of attention, imagery, and feelings [30]. Narrative communication messages either convey a point to another party or receive information from another party [31]. Narratives are a scientific way of relying on empirical and experimental methods to discover, describe, or elucidate some domain of interest through which we develop our understanding of the world and the distinctive ways of constructing reality [29,32]. One’s engagement with a narrative may result in one’s endorsement of modified attitudes and behaviors [33]. Engagement is affected by the attentional focus and one’s identification with the narrative [34]. Prior studies that tested the effect of narrative persuasion, however, did not focus on health [35,36]. Narrative messages may be effective in the health-behavior context, as they are the basic mode of human interaction that we use in our day-to-day lives to influence others [32].

Narrative messages in health communication entail anecdotes, testimonials, and stories [33]. In health communication several moderators were found to shape the narrative’s extent of persuasion: the health behavior, the delivery channel, the research design and the sample characteristics [35]. Previous studies tested the effect of narratives on health-related attitudes and intentions which were strongly associated with health behaviors [37-42].

Previous studies relied on behavioral modeling of exemplars with whom the audience identified [43,44]. Identification with an exemplar was key in the persuasion effect the narrative yielded [38,40,45-47]. Narratives of an exemplar delivered via audio and video which aimed at prevention, had a greater persuasion effect than did print-based narratives aiming at cessation [35]. Crafting engaging narratives, however, requires lengthy stories which are hard to apply in public health communication [43]. Some brief print-based narrative messages regarding risks of type 2 diabetes may have a stronger effect than will others.

Hypothesis 1

Different narrative communication messaging will have a different effect on perceived risks of Type 2 diabetes. Since the narrative persuasion theory is interpretive, it explores the impact of each message asking: for whom; under what circumstances; how; and when does each message achieve optimum effects [48,49]. The extent to which narrative messages regarding risks of type 2 diabetes will influence individuals may, therefore, differ among them. Narrative messages that are employed specifically for type 2 diabetes, could be more effective than general health related messaging because they touch on well-known determinants of type 2 diabetes. We hypothesize that the ability of narrative messages to raise awareness of type 2 diabetes risks, may depend, in part, on the extent to which people “identify” with the different narrative messages [31]. Narrative messaging, therefore, may carry a different appeal to homogeneous groups of people who are defined by similarity in their pattern of responses to narrative persuasion messages (i.e. mindset-segments) regarding risks in type 2 diabetes.

Hypothesis 2

Different narrative communication messages regarding risk of type 2 diabetes will carry a different appeal for different people by mindset segments. Narrative messages may also impact beliefs of healthy individuals about who is responsible for addressing and engaging in health behaviors, thereby, shaping their perceptions about their risks of type 2 diabetes [50].

Hypothesis 3

Different narrative communication messages will have a greater impact on perceived responsibility for health behaviors to avoid risks of type 2 diabetes.

The Current Study

Studies that tested the effect of specific print-based narrative messaging on identification and on attitudes towards the messaging by mindset-segmentation regarding urgent health problems are scant [35]. This study is in response to previous calls to explore under what condition a print-based narrative messaging may influence attitudes [35]. This study attempts to explore the effect of various elements of narrative messaging on the identification with the message and on risk awareness. While previous studies mostly included lab experiments or field experiments, this study employs an experimental research design [35]. This study is an important step in beginning to close the literature gap by testing specific brief narrative messaging for awareness of type 2 diabetes risk among healthy people. The aim of this study was to fill the above theoretical, methodological and practical gaps in the state of the art. Theoretically, to best of our knowledge, studies that tested specific narrative messaging for healthy populations regarding risks of type 2 diabetes are scant [29]. Also, the application of the narrative persuasion theory in the context of diabetes prevention while measuring one’s identification with elements of the message is an underutilized and underexplored research area [43]. Methodologically, we test unexplored communication messages among healthy individuals through a multi-disciplinary view, examining narrative messaging from different perspectives. In terms of practice, this research project assesses the impact of a variety of narrative messages as drivers of perceived risk of type 2 diabetes and proses to apply the knowledge by a classification tool developed based on the impact of the narrative communication messages.

Research Design and Methods

Conjoint measurement refers to a class of research procedures in which the respondent is provided with a set of systematically varied combinations of features (questions and answers) and rates the combination, providing an estimate for the part-worth utility of each answer [51]. Since our objective is to develop a model of messaging for each respondent, the question of sample size devolves into a question of the number of respondents needed before the average model across respondents becomes stable [52]. Whereas sociologists study behaviors of large groups of people and deal with the percent of people who achieve a given score, experimental psychologists deal with individual behavior focusing on the magnitude of a response and looking at means, and the stability of the mean as a predictor of the performance of the dependent variable. Thus, in Mind-Genomics, since results are based upon the average rating assigned to a narrative statement, the size of the sample is not a question of the stability of the average rating, but rather the stability of the model averaged across the different respondents. Data on utilities from several conjoint measurement samples confirm previous observations on base size studies and indicates that much of the information can be obtained with lower bases than the typical base size and the same conclusions can be made with base sizes around 50 [53]. Therefore, the sample comprised 50 respondents, healthy American adults with 25 females and 25 males, ages 31-44 (n=12); 45-55 (n=18) and 56+ (n=18). Respondents were selected by Luc.id, Inc., a panel provider of on-line samples. Respondents represent a cross-section of the typical respondent.

We structured messages that tell a story and attend to coherent statements with a clear beginning, middle, and end [54,55]. We designed the narrative messages and shaped the rating question to influence cognitive attention, thereby, mediating between the content and the intention. Since narrative communication messaging that relates to only one perspective, may carry bias, reducing the complexity in our world and inhibiting effective awareness for different target audiences, this study combines among narrative persuasion messages from several perspectives: the psychological perspective (individual’s behavior), the sociological perspective (perceived contextual factors), the economics perspective (social structural elements and costs) and the health management perspective (health services). We structure messages by an experimental design guided by Mind-Genomics®, a new conjoint based scientific approach, best described a ‘cartography of the mind.’ Mind-Genomics® examines responses of people to different stimuli in daily life [56]. Mind-Genomics maps an experience by identifying its different facets, determining to what facets the person attends, and how important each facet is for each person. Mind-Genomics® reveals how people react to the specifics of the messaging, looking at the nuances, whereas accounting for the richness of the experience. Mind-Genomics® segments different groups of people by their different viewpoints, so-called mindsets.

Outcome and Independent Variables

The dependent variable is perceived risks of type 2 diabetes, measured by the extent of importance each respondent attributes to each driver of risk on a 1-9 rating scale. Four categories of narrative statements: determinants of type 2 diabetes, healthcare needs, expectations and support and responsibility. Each category comprised four narrative messages about type 2 diabetes, each from different disciplines. Each respondent evaluated a unique set of 24 combinations of narrative messages that are each independent of all other messages by experimental design, with each category comprising a minimum of two statements, or a maximum of four statements. By virtue of the Mind-Genomics® experimental design, the 16 messages are statistically independent of each other. The structure of the 24 combinations remained the same, ensuring statistical independence of the predictor variables for subsequent regression. Effective messages regarding risks of type 2 diabetes need not only proper framing, but also avoiding the activation of negative attitudes and resistance to the message itself [57]. The specific combinations changed, however, due to a permutation scheme allowing the experiment to cover many more of the possible combinations of messages using today’s standard experimental designs [57,58].

With 50 respondents, the researcher covers 1200 messages (50×24), rather than repeating the same 24 messages 50 times. Table 1 presents categories and messages per category. Respondents rated the importance of each message in shaping their perceived risk of type 2 diabetes on a 1-9 rating scale. Response biases were overcome by presenting the respondent with combinations of messages assembled by an experimental design, which mixes and matches different types of ideas to test combinations of messages by categories that drive the perceived risk of type 2 diabetes [20,31]. To test the instrument, reliability was established by the split-half method. The entire data set was divided into two equal groups, with each respondent contributing data equal to both groups. Each group is used to estimate the coefficient of the messages. Three sets of coefficients were created: from the total panel, and from each half-set. The two half sets of data were highly correlated with data for the total panel (0.90 for group 1; 0.87 for group 2).

Table 1: The Four Categories and the Four Narrative Messages in Each Category.

Statistical Analysis

The experimental design ensures that an individual-level regression model can be run on the data. The original 9-point rating scale, anchored at both ends, was transformed to a binary scale (i.e., Ratings of 1-6 were considered ‘not important,’ and transformed to 0. Ratings of 7-9 were transformed to 100), to denote that these were important. The data were then subject to Ordinary Least-Squares regression (OLS). The regression equation was run for total panel and for each key subgroup (total, gender, age), incorporating all relevant data into one regression model for the group. Whereas the regression model suggests that a standard error around 4.0 or so characterizes the different coefficients, as a rule of thumb in conjoint coefficients of 8 or higher tend to be statistically significant and to co-vary with measurable external behavior which might serve as a validation.

In conjoint analysis, regression coefficients reveal the impact (degree of agreement) of communications of messages. The pattern of strong performing (positive) coefficients across different subgroups, suggest the nature of what is important for the respondents who are assigned to a mindset which is created by clustering the coefficients across all of the messages. There is no need for Beta values for the coefficient because in the modeling the messages are represented as either 0 (absent from the combination) or 1 (present in the combination) [57].

Results

The rated importance of the information presented by the narrative message on type 2 diabetes varied across groups. Respondents in the youngest group rated information as unimportant. Members of the other age groups rated the information as moderately important and very important. Males had a higher additive constant indicating that they will require less specific information to reach risk awareness than will females. The differences in response patterns of different groups showed that there are three distinct mind-sets. Table 2 presents the coefficients for the total panel and for the three mind-set segments reflecting different patterns of responses to the importance of each narrative statement contributing to the perceived risk as emerged from Mathematical K-clustering analysis. Figure 1 presents sample distribution by mind-set segments and Figure 2 presents sample distribution into mindset-segments by age group.

Table 2: Coefficients for total panel and the three emergent mindsets based upon the patterns of coefficients of narrative messages.

Figure 1: Risk Awareness of Type 2 Diabetes in Healthy Individuals.

Figure 2: Distribution into Mindsets by Age.

Applying Narrative Communication Messaging for Raising Awareness to Type 2 Diabetes

To identify which communication messaging should be used in practice, we applied the personal viewpoint identifier (PVI) which is created a new for each study and in this case revealed the mind-set of an individual through a simple, 30-second interaction. The respondent completed a short, 6-question evaluation, with the pattern of the responses linked to membership in one of the three mind-sets. The six most discriminating narrative messages were chosen to create the PVI which then created a binary scale on which new participants may rapidly indicate their answers. Based on these answers, the Mind-Genomics system instantly presents the sample mind-set membership for the individual in the population, who can then be given the most effective messaging for the mind-set to which the individual appears to belong. The PVI is available at: http://162.243.165.37:3838/TT37

Discussion

This study tested narrative persuasion messages as drivers of public awareness of risks of type 2 diabetes. This study makes theoretically, methodologically and practical contribution. Theoretically, this study extended the narrative persuasion theory testing narrative communication messaging in the health context, focusing on risk awareness in type 2 diabetes among healthy people. Methodologically, this study explored narrative communication messaging through a multi-disciplinary view, from different perspectives applying an innovative conjoint-analysis procedure. Practically, findings direct professionals on a local level and on a national health policy level to use narrative communication messaging that impact the risk perception of healthy people, by mind-set segments, regarding type 2 diabetes. Findings show that all study hypotheses were corroborated and also suggest that just as narrative messaging was effective in public campaigns on general health issues, it can be effective for public campaigns targeting awareness of risks in type 2 diabetes for the healthy population [21].

As for hypothesis 1, stating that different narrative communication messaging will have a different effect on perceived risks of type 2 diabetes, findings suggest that a number of narrative messages, that may be used on local level by professionals appear to be ineffective, and may create antagonism and anxiety, rather than raise public awareness of risks of type 2 diabetes and navigate individuals towards the adoption of healthy behaviors. Such messages are: People with type 2 diabetes use a lot of health services; Type 2 diabetes requires lots of medications; Type 2 diabetes is the most profound disease of this century and; living longer raises the risk of suffering from Type 2 diabetes. This finding may be attributed to the underlying communication orientation in these narrative messages. Ineffective messages fall under the category of content-oriented messaging which focuses on ‘what the public should know about type 2 diabetes’. Whereas content-oriented messaging is popular, it does not promote behavioral change, particularly compared to change-process oriented communication which was found to be a ‘make or break’ factor in behavioral modifications, including in type 2 diabetes [56,57].

As for hypothesis 2 stating that different narrative communication messages regarding risk of type 2 diabetes will carry a different appeal for different people by mindset segments, data show that response patterns to narrative messages differed among groups of people, differentiating them by mindset segments. People who are members of mind-set1 will react to messages depicting individuals as having control and able to take responsibility for their health stressing the psychology view (e.g., Diet and exercise are key to type 2 diabetes prevention; Type 2 diabetes is dangerous without treatment). This finding supports previous findings on the role of communication in promoting perceived control in behavioral modifications [56,57]. Outreach to people belonging to mindset l should entail information on: steps in the behavioral change process; what may assist them throughout the change process; what internal and external resources they may use; and how they may overcome barriers [58].

Messaging is to be inspirational and hopeful enhancing self-efficacy [57,58]. People who belong to Mindset2, the smallest mindset segment, will positively react to narrative messages depicting the doctor as a resource stressing the sociological view (e.g., A doctor should refer patients to educational materials about type 2 diabetes; It’s the doctor’s role to educate patients about type 2 diabetes; A patient should know all the possible treatments of type 2 diabetes). This finding supports previous studies on the sociological role of trust in physicians and the public expectation from physician to inspire them in adopting healthy behaviors [57,59].

People who are members of Mindset 3, will positively react to narrative messages depicting help from others stressing the economics and health management view (e.g., Participation in workshops helps prevent type 2 diabetes; Belonging to a community helps maintain healthy behaviors to prevent type 2 diabetes; learning how others cope with challenges is beneficial), focusing on community and available supporting health services. These findings support previous studies that claimed that communication messaging in national public campaigns may improve awareness of type 2 diabetes risks in healthy populations and among different segments of the population [23,29]. Study findings echo previous findings on the strong impact that narrative messaging may have on attitude change and behavioral modifications [29,31]. As for hypothesis 3, stating that different narrative communication messages will have a greater impact on perceived responsibility of individuals to modify their health behaviors and avoid risks of type 2 diabetes, the membership of people to mindset-segments entailed differences in their perceived responsibility. Perceived responsibility for reducing risks of type 2 diabetes ranged from self- responsibility (segment 1) to doctor’s responsibility (segment 2) and to community as having a role in helping its healthy members prevent risks of type 2 diabetes. Findings support previous studies stating that narrative messaging may play an important role in health communication campaigns to influence attitudes, intentions, and health behaviors [35].

Practice Implications

The knowledge derived from this research enables policy makers to accord the most effective narrative communication messaging to each person and group in the population, by the mind-set segmentation, in the sample. The segmentation by mindset suggests that a public communication campaign with the same messages for all, will be futile. When designing campaigns to raise public awareness of risks of type 2 diabetes, content-oriented messages should be omitted. Figures 1 and 2 indicate that segments of mindsets1 and 3 are about the same size but as age increases, on one hand the perceived importance of this information increases but perceived individual’s responsibility to modify risk behaviors decreases. People in the oldest group (56+) who are under the highest risk of type 2 diabetes, attribute the highest authority to doctors compared to people in other age groups and expect support of doctors, the community and health services (i.e. workshops) in behavior modification to prevent type 2 diabetes. These data suggest that in campaigns targeting people who are older than 45 years old, messaging is to be based on the change-process orientation rather than content-oriented. Last, three campaigns are to be designed, each targeting people in a different mindset segments and each focusing on a different perspective. One campaign entailing messages of perceived control over health (psychology), another campaign entailing messages of advice from trusted professionals (sociology) and the third campaign offering health-services (i.e., workshops and mentorship of supporting individuals) (health management) for maintaining healthy behaviors.

Future Studies

Future studies may continue to test unique features of brief printed-based narrative messaging and their effect on health attitudes and intentions. Future studies may also broaden our knowledge as to the effect of culturally tailored messaging on risk awareness in urgent health problems.

Conclusion

To sum, this study closed a knowledge gap in the state of the art examining multi-perspective narrative persuasive messaging as means to raise awareness of type 2 diabetes in healthy populations. This study presents a new approach to raise public awareness of risks of type 2 diabetes through narrative messaging by mindset segmentation. To enhance effectiveness in raising awareness of type 2 diabetes risks and to wisely allocate budgets, health professionals, policy makers and public campaign designers, are urgently called upon to use the VPI, ask the right few questions to identify the belonging of each individual in the healthy population to a mindset segment in the sample and use the appropriate narrative communication messaging per segment in raising awareness. The theoretical, methodological and practical knowledge derived from this study will enable policy makers and professionals to accord the most effective narrative communication messaging to each person and group in the population, by the mindset segmentation, in a cost-effective manner.

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DOI: 10.31038/EDMJ.2020443

Abstract

Advanced age and medical co-morbidity are strong predictors of mortality in COVID-19 infection. Yet few studies (to date) have specifically addressed risk factors associated with COVID-19 mortality in a high-risk subgroup of older US adults having one or more chronic diseases. Our hypothesis is that medications having ‘off-target’ anti-inflammatory effects may play a role in modulating the immune response in COVID-19 infection. We analyzed baseline risk factors associated with respiratory failure or death in 55 older adult US military veterans hospitalized for COVID-19 infection during (March-June 2020) the peak of the pandemic in New Jersey. Fifty-three percent (29/55) of patients experienced respiratory failure and thirty-one percent (17/55) died. In adjusted logistic regression analysis, baseline neutrophil to lymphocyte ratio (NLR) (P=0.0035) and body mass index (P=0.03) were significant predictors of the risk for respiratory failure. Age (P=0.05) and non-use (vs. use) of psychotropic medications having serotonin 2A receptor antagonist properties (odds ratio 5.06; 95% confidence intervals 1.18-21.7; P= 0.029) was each a significant predictor of an increased risk of death. There was a significant interaction effect of age and non-use (vs.. use) of psychotropic serotonin 2A receptor antagonist medications on the odds ratio (OR) for death (P=0.011). In selected, ventilator-dependent COVID-19 pneumonia patients treated with psychotropic serotonin 2A receptor antagonist medications to control agitation and ICU delirium, there was an apparent positive association between medication use and significant rise in the absolute lymphocyte count and decrease in the neutrophil: lymphocyte ratio. Taken together, these data are the first to suggest that certain psychotropic medications used in the treatment of chronic psychiatric illness and/or for acute delirium are inversely associated with mortality in severe COVID-19 infection by unknown mechanism which may involve (in part) immunomodulatory effects.

Introduction

According to the Centers for Disease Control [1], medical co-morbidity was associated with a substantially increased risk of admissions to the ICU due to severe COVID-19 infection. Hypertension, diabetes and advanced age were among the risk factors associated with increased mortality due to severe COVID-19 infection in a recent large study from metropolitan New York [2]. Older adult U.S. military veterans carry a substantial burden of medical co-morbidities including type 2 diabetes mellitus and hypertension [3]. Yet few studies to date have examined risk factors predictive of severe COVID-19 infection in patients having one or more chronic illnesses. The aim of the present study was to evaluate risk factors associated with poor outcome in COVID-19 infection requiring hospitalization in older adult US military veterans. The SARS-Cov-2 virus mediates hyper-inflammation and dysregulated immunity leading to ‘cytokine storm’ [4]. Inflammation predisposes to hypercoagulability and platelet-derived serotonin (5-HT) promotes neutrophil infiltration at sites of injury, each process is recognized as a ‘bad actor’ in severe COVID-19 infection [5]. The 5-hydroxytryptamine 2A receptor is expressed on platelets, innate and adaptive immune cells [6,7] and it was reported to ‘drive’ chronic inflammation in animal models of autoimmune diseases [8,9]. A secondary aim of the present study was to test whether psychotropic medications belonging (in part) to the class of 5-hydroxytryptamine 2A receptor antagonists (in current use as anti-depressant or atypical antipsychotic medications) may modify the risk of death in severe COVID-19 infection.

Patients and Methods

The retrospective study was reviewed and approved by the local Veterans Affairs New Jersey Healthcare System Institutional Review Board. Patients were consecutively selected from among those inpatients admitted to an acute medical ward or intensive care unit (ICU) at the Veterans Affairs New Jersey Healthcare System (VANJHCS), East Orange campus between late March 2020 and early June 2020, i.e. during the peak of the pandemic in New Jersey. Nearly all patients tested COVID-positive (n=53) by polymerase chain reaction of an oropharyngeal or nasopharyngeal swab. Two patients had a clinical picture consistent with COVID-19 pneumonia, but a negative COVID-19 PCR test and were included in the analysis. Ninety-six percent of patients were men. Forty-one of 55 patients (75%) had respiratory symptoms on admission. Thirty-four percent of patients were 74 years or older, nearly all patients had at least one co-morbidity, including forty percent of patients who had a baseline history of cardiovascular disease (Table 1).

Table 1: Baseline clinical characteristics in the study patients.

N=55 patients; BMI: Body Mass Index; ACEi: Angiotensin Converting Enzyme Inhibitor; ARB: Angiotensin Receptor Blocker Medication; AA: African-American, NHW: Non-Hispanic White, H: Hispanic; COPD: Chronic Obstructive Pulmonary Disease; ESRD: End Stage Renal Disease.

Endpoint(s)

Twenty-nine of fifty-five patients (52.7%) experienced respiratory failure and there were 17 deaths which generally occurred within 2-3 months of the acute COVID-19 hospitalization. Unless a patient was readmitted to the same institution (VANJHCS), or had subsequent entries in the VANJHCS medical record, he or she was presumed to have survived acute episode of COVID-19 infection following his or her successful discharge home or to a lower-intensity, rehabilitative-type care facility.

Respiratory failure is defined as requiring intubation and mechanical ventilation or high-flow, concentrated oxygen, e.g. 50% oxygen via nasal cannula at 15 liters/min or > 50% oxygen via a non-rebreather mask.

Diabetic microvascular complications – retinopathy – macular edema, or proliferative retinopathy, nephropathy – >300 mg/g creatinine albuminuria; painful neuropathy – evidenced by treatment with gabapentin and clinical diagnosis determined by trained neurology staff. Neutrophil/Lymphocyte ratio (NLR) – is the average on two consecutive days of the absolute neutrophil count/absolute lymphocyte count which occurred at the nadir of the absolute lymphocyte count.

Clinical and other laboratory data was extracted from retrospective chart reviews. Body weight index (BMI), glycosylated hemoglobin value was based on prior results closest to the date of inpatient admission. Baseline insulin use or the use of angiotensin converting enzyme inhibitor or angiotensin receptor blocker medications was determined from baseline outpatient medication lists.

Patients Treated with Antipsychotic or Antidepressant Medications

Treatment with an atypical, second-generation antipsychotic medication (SGA) or an antidepressant medication that has antagonist activity at the 5-hydroxytryptamine (serotonin)2A receptor was evaluated as a possible risk factor for the outcome of death vs. survival after acute COVID-19 infection. Both atypical antipsychotics and certain anti-depressants (tricyclic antidepressants, trazadone, mirtazapine) share high-affinity antagonism on the 5-hydroxytryptamine 2A receptor. Total twenty patients were treated with a SAG antipsychotic medication (risperidone, olanzapine, quetiapine, aripiprazole) and five were treated with one of the 5-HT2AR antagonist antidepressant medications (trazadone, mirtazapine) either for an underlying mental health disorder (schizophrenia, schizoaffective disorder, major depressive disorder) or to manage acute agitation/delirium.

Statistics

Logistic regression analysis was used to model possible baseline risks factors associated with the occurrence of respiratory failure or death. Age and body mass index were included as covariates in the model when testing for an effect of other risk variables. In univariate regression analysis, other risk variables [NLR, diabetes mellitus, baseline use of various medication classes, baseline cardiac disease] were tested for association with the endpoint, and were included in the model if it reached 0.05 of significance level. Two way-interactions were checked among significant risk variables. Logistic regression was conducted using SAS 9.4 (SAS Institute Inc, Cary, NC).

Results

The baseline clinical characteristics in the study patients are shown in Table 1. The mean age was 70.6 ± 11.5 years old. More than half of the patients had diabetes mellitus (nearly all type 2 DM) and one in four patients were treated with insulin. Mean glycosylated hemoglobin was 7.7 ± 2.0% among diabetic patients and one-third had at least one microvascular complication (not shown in Table 1).

Lymphopenia is a characteristic laboratory feature in severe COVID-19 disease. The neutrophil to lymphocyte ratio (NLR) was reported to be a prognostic marker in COVID-19 infection: a threshold NLR value >5.0 vs. ≤5.0 demonstrated high sensitivity and specificity for differentiating between severe and mild COVID-19 infection [10]. In univariate regression analysis, the neutrophil: lymphocyte ratio (Odds ratio: 1.232; 95% confidence intervals 1.079-1.406; P=0.002) was a significant predictor of the risk for respiratory failure (Table 2A).

In multivariate logistic regression that adjusted for age and body mass index, baseline NLR (OR 1.2554; 95% CI: 1.0776-1.4624; P=0.0035) and BMI (OR 1.1429; 95% CI: 1.0131-1.12893; P=0.030) was each a significant predictor of the risk of respiratory failure in COVID-19 infection (Table 2B).

Table 2: Univariate (A) and multivariate (B) logistic regression of risk factors associated with Covid-19 respiratory failure.

N=55; NLR: Neutrophil to Lymphocyte Ratio; CI: Confidence Interval.

N=55; NLR: Neutrophil to Lymphocyte Ratio; CI: Confidence Interval.

We next evaluated risk predictors of COVID-19 mortality. In univariate logistic regression analysis, the use of an antipsychotic or antidepressant medication having 5-HT2A receptor antagonist properties (OR 0.198; 95% CI:0.038-0.634; P=0.0094) was a significant predictor of a decreased risk of death (Table 3). Age (OR 1.076; 95% CI 1.015-1.141; P=0.0139) was a significant predictor of an increased risk of death (Table 3). Baseline cardiac disease (OR 3.095; 95% CI 0.948-10.109; P=0.0613) was a nearly significantly predictive of an increased risk of death (Table 3).

Table 3: Univariate logistic regression analysis of risk factors associated with Covid-19 death.

BMI: Body Mass Index; dz: Disease; *Second generation atypical antipsychotics, tricyclic antidepressants, trazadone or mirtazapine; CI: Confidence Interval, N=55 patients.

In multi-variate logistic regression analysis, non-use of antipsychotic or antidepressant medications having 5-HT2AR antagonist properties (OR 5.058; 95% CI: 1.180-21.689; P=0.029) and age (OR 1.062; 95% CI: 1.000-1.128; P=0.050) was each a significant predictor of an increased risk of death in COVID-19 infection (Table 4A).

There was a significant interaction effect of age and 5-HT2A receptor-blocking classes of medication on the risk of death in COVID-19 infection (P=0.0112) (not shown in Table 4). Use of 5-HT2A receptor blocking medications was associated with low mortality rate (0/18) in younger patients (≤72 years old) and the overall mortality rate (3/8) increased among patients aged 73-95 years old treated with a 5-HT2A receptor blocking class of medication (not shown in Table 4).

Table 4: Multivariate logistic regression analysis of risk factors associated with Covid-19 death.

N=55 patients; *Second generation atypical antipsychotics, tricyclic antidepressants, trazadone or mirtazapine; CI: Confidence Interval.

In representative patients having hypoxemic respiratory failure, treatment with psychotropic medications having 5-HT2A receptor blocking activity (to control agitation and/or delirium on the ventilator in the ICU) was associated with an abrupt increase in the absolute lymphocyte count and a decrease in the NLR.

Case 1

A 59-year old female with systemic lupus erythematosus developed hypoxemic respiratory failure. She manifested a high level of systemic inflammation, an initial C-reactive protein level > 320 mg/L, normal (1-10) and 2 weeks later it was still 189 mg/L. She was treated for 3 weeks with a nightly dose of an oral SGA to manage agitation/delirium on the ventilator in the ICU. Her absolute lymphocyte count increased from 0.9 to 3.7 K/cm2 in association with SGA treatment (solid line, Figure 1). She was discharged to a rehabilitation center in stable condition.

Figure 1: A 59-year old woman with systemic lupus erythematosus who developed hypoxemic respiratory failure. Solid line indicates nightly treatment with an oral second-generation anti-psychotic medication. The absolute lymphocyte count increased from 0.9 to 3.7 K/cmm in association with SGA treatment. The patient was discharged to a rehabilitation center in stable condition.

Case 2

A 55-year old man with T2DM experienced hypoxemic respiratory failure. The initiation of nightly atypical antipsychotic medication was associated with an abrupt rise in absolute lymphocyte count (solid bar, Figure 2A). The absolute lymphocyte count was significantly higher (Figure 2B) and the NLR was significantly lower (Figure 2C) during 7 days on SGA treatment compared to corresponding mean level 4 days before initiation of SGA treatment.

Figure 2: A 55-year old man with type 2 diabetes mellitus (T2DM) who developed hypoxemic respiratory failure. A) The initiation of treatment with nightly atypical, second-generation antipsychotic medication was associated with an abrupt rise in absolute lymphocyte count (solid bar). B) The absolute lymphocyte count was significantly higher and C) the NLR was significantly lower during 7 days on SGA treatment (Medication) compared to corresponding mean level on 4 consecutive days before initiation of SGA treatment (Medication).

Case 3

A 76-year old man with T2DM and polyneuropathy developed hypoxemic respiratory failure and was intubated. During the initial 15 days he was treated with a combination of D2 receptor blockers (Haldol) and benzodiazepines to control agitation/delirium in the ICU on the ventilator (dashed line, Figure 3A). Three days after successful extubation (arrow, Figure 3A) the drug regimen was changed and he received an 18-day course of an oral SGA medication nightly to control agitation/delirium (solid line, Figure 3A). He was later discharged (in stable condition) from the hospital. The mean absolute lymphocyte count was significantly higher during a 16-day period on daily treatment with an SGA compared to the mean level during a comparable, preceding 16-day period on intermittent D2 receptor antagonist and/or benzodiazepine medications (Figure 3B).

The mean neutrophil/lymphocyte ratio (NLR) was significantly lower (6.6 vs. 18.0; P < 0.001) during the period on treatment with an SGA (atypical antipsychotic medication) compared to the corresponding preceding period on D2R antagonist and/or benzodiazepine medications to control agitation and delirium (Figure 3C).

Figure 3: A 76-year old man with T2DM who developed hypoxemic respiratory failure and was intubated. A) During initial 15 days he was treated with a combination of D2 receptor blockers (Haldol) and benzodiazepines to control agitation/delirium in the ICU on the ventilator (dashed line). Following extubation (arrow) the drug regimen was changed to a nightly dose (for 18 consecutive days) of an oral SGA medication to control agitation/delirium (solid line). He was later discharged (in stable condition) from the hospital. B) The mean absolute lymphocyte count was significantly higher during a 16-day period on daily treatment with an SGA compared to the mean level during a comparable, preceding 16-day period on intermittent D2 receptor antagonist and/or benzodiazepine medications. C) The mean neutrophil/lymphocyte ratio (NLR) was significantly lower (6.6 vs. 18.0; P < 0.001) during the period on treatment with an SGA (atypical antipsychotic medication) compared to the corresponding preceding period on D2R antagonist and/or benzodiazepine medications to control agitation and delirium.

Discussion

Biomarkers that predict an increased risk of severe COVID-19 infection can help guide therapy in selected patients. The present finding that the baseline neutrophil to lymphocyte ratio was a significant predictor of the risk for respiratory failure in older adult hospitalized patients suffering with COVID-19 pneumonia is consistent with other reports of the prognostic value of the NLR [10]. Yet, to our knowledge, this is the first report that treatment with certain psychotropic medications having 5-HT2A receptor blocking properties was associated with substantially lower mortality in severe COVID-19 infection. The apparent association between the use of these classes of medications (to control delirium and agitation in the ICU) and higher absolute lymphocyte count and lower NLR suggests a possible immunomodulatory role for 5-HT2AR antagonists. In a mouse model of autoimmune hepatitis, treatment with the 5-HT2AR blocking anti-depressant medication mirtazapine substantially lowered hepatic inflammation [8]. Other evidence derived from in vitro and animal studies [6,7,9] suggests that 5-hydroxytryptamine 2A receptor antagonism may mediate an anti-inflammatory effect in part by interfering with the elaboration of pro-inflammatory cytokines from innate immune cells, e.g. macrophages. Despite unexplained lymphopenia, T-cell activation is another characteristic immunologic feature in severe COVID-19 infection [4]. The 5-hydroxytryptamine 2A receptor is widely expressed on peripheral immune cells (B cells, T cells) and vascular cells and among the diverse reported effects of 5-HT and/or the 5-HT2A receptor are: T-cell activation [11] and increases in pro-inflammatory cytokines IL-6, interferon-gamma, and interleukin-2 [7,8].

Second-generation, atypical antipsychotic medications, tricyclic antidepressants and other antidepressant medications useful in treatment-resistant depression (trazadone, mirtazapine) all share high affinity for the 5-HT2A receptor. Several of the SGA medications also target the D2 dopamine receptor, the H1 histamine receptor, the alpha-1 adrenergic receptor, and the muscarinic acetylcholine receptor-making it difficult to ascribe a putative beneficial effect solely to actions at the 5-HT2A receptor. Yet (in our study) even administration of low doses of the antidepressant trazadone (relatively selective for 5-HT2AR antagonist activity) appeared to significantly upregulate lymphocyte count and downregulate the NLR within a time period (7-8 hours) consistent with the half-life of the medication.

Many of the patients in the present study having co-morbid psychiatric illness were treated (before and during COVID-19 infection) with an SGA or anti-depressant medication having serotonin 2A receptor antagonist properties. These patients tended to experience a less severe form of illness in which the baseline NLR was generally < 10. Mean baseline NLR did not differ significantly between patients who were treated or not treated with psychotropic medication having serotonin 2A receptor antagonist properties. In our multi-variate logistic regression model that included adjustment for baseline NLR, 5-HT2AR antagonist medication use (vs.. non-use) was still a significant predictor of a lower risk of mortality. Taken together, there did not appear to be a selection bias toward use of 5-HT2AR antagonist medications in patients with less severe form of COVID-19 infection.

The present retrospective study was not designed to test for a possible causal relationship between the use of 5-HT2AR antagonist-like medications and mortality in severe COVID-19 infection. There are caveats important in the interpretation of the present findings: first, patients having co-morbid schizophrenia or major depression were generally younger compared to the overall patient cohort and second, certain genetic and/or environmental factors (including unknown immune factors) previously associated with an increased risk of psychiatric disorders may have independently affected mortality risk in COVID-19 pneumonia.

The study has several limitations. It was small and the results may only apply to the experience of older adult men having a number of different co-morbidities (diabetes, advanced age, hypertension, cardiovascular disease) previously associated with a higher risk of death in COVID-19 infection. More study in a larger group of patients (including women and patients having fewer co-morbidities) is needed to determine the generalizability of the findings.

In summary, advanced age and the non-use of certain antipsychotic and anti-depressant medications having shared antagonist activity on the 5-HT2A receptor was each a significant predictor of an increased risk of death in a small cohort of hospitalized, older adults who experienced COVID-19 infection requiring hospitalization. A future randomized trial may help determine whether an apparent association between the use of these classes of ‘anti-inflammatory’ medications and improved immunological parameters may translate into lower COVID-19 mortality in a subset of severely-affected patients.

Acknowledgements

We thank the dedicated and caring nurses, physicians, hospital workers and administrators at the Veterans Affairs New Jersey Healthcare System for their tireless and compassionate efforts on the part of the veterans and other patients affected by the COVID-19 pandemic. The views expressed here are solely those of the authors and do not represent the official position of the U.S. Department of Veterans Affairs or the US Government.

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