Addiction as a Coping Response: Hyperkatifeia, Deaths of Despair, and COVID-19
Authors: George F. Koob, Patricia Powell, Aaron White
Journal: American Journal of Psychiatry (2020)

Back to table of contents Previous article Next article Reviews and OverviewsFull AccessAddiction as a Coping Response: Hyperkatifeia, Deaths of Despair, and COVID-19George F. Koob, Ph.D., Patricia Powell, Ph.D., Aaron White, Ph.D.George F. Koob, Ph.D., Patricia Powell, Ph.D., Aaron White, Ph.D.Published Online:1 Nov 2020https://doi.org/10.1176/appi.ajp.2020.20091375AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Neuroadaptations that occur in response to repeated substance use diminish the euphoria that is produced by the acute use of a drug and increase levels of physical and emotional stress between drug use episodes. An individual who struggles with addiction can be tempted to return to drug use to reduce misery that is caused by use of the drug itself. Recent developments, including an increase in "deaths of despair" in the United States, increases in alcohol use by some individuals as a result of the 2019 coronavirus disease (COVID-19) pandemic, and limited availability of in-person treatment and recovery support, raise concerns about the use of alcohol and other drugs in an effort to cope with distress. In this article, we examine the role of negative reinforcement in the development of addiction, discuss neuroadaptations that lead to increases in emotional and physical misery between episodes of drug use, and explore how using substances to cope with the emotional strain of social isolation and financial uncertainty during the COVID-19 pandemic could contribute to deaths of despair.Conceptual Framework of AddictionAlcohol Use Disorder as a Prototype AddictionAlcohol use disorder (AUD) can be defined as a chronically relapsing disorder that is associated with compulsive alcohol drinking, the loss of control over intake, and the emergence of a negative emotional state when alcohol is no longer available. Patterns of alcohol use in AUD can range from intermittent episodes of binge alcohol intake to prolonged heavy drinking over longer periods that progresses to continual drinking for fear of withdrawal. Comorbid affective disorders, a history of trauma, and exposure to stressors increase the likelihood of developing AUD (1, 2). Abstinence from such alcohol binges or chronic high alcohol intake is characterized by a withdrawal syndrome with severe emotional and somatic symptoms and intense craving for alcohol. Negative emotional states commonly trigger relapse (3, 4), and such negative emotional states can be driven by excessive alcohol consumption itself. Like other substance use disorders, AUD is now considered a spectrum disorder, as described in DSM-5 (5), which provides a framework for determining the intensity of the disorder based on the number of symptoms the individual presents.Heuristic Framework for AddictionA heuristic framework for studying addiction, characterized by a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—provides a starting point for exploring our theme in this article, namely, the intersection between alcohol addiction, deaths of despair, and social isolation that are caused by the COVID-19 pandemic (6, 7). Under this framework, dysregulation occurs in three functional domains that reflect the three stages of the addiction cycle: incentive salience/pathological habits in the binge/intoxication stage, negative emotional states in the withdrawal/negative affect stage, and executive function deficits in the preoccupation/anticipation stage. These three domains and stages are hypothesized to be mediated by three major neurocircuitry elements: basal ganglia, extended amygdala, and prefrontal cortex, respectively (6). An individual can enter the addiction cycle at any of these three stages (6) (Figure 1).FIGURE 1. Conceptual framework for the neurobiological basis of substance use disordersaa The framework involves a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three stages involve dysregulations in three functional domains (incentive salience/habits, negative emotional states, and executive function) that are mediated by three major neurocircuitry elements (basal ganglia, extended amygdala, and prefrontal cortex, respectively). The negative emotional state of drug withdrawal, termed hyperkatifeia, can be facilitated and exacerbated by non-drug-related allostatic loads, such as genetics, epigenetics, childhood trauma, and psychiatric comorbidity, in addition to excessive drinking. Hyperkatifeia in turn drives the negative reinforcement source of motivation for compulsive-like alcohol seeking and using. Hyperkatifeia can drive impulsivity via negative urgency that is associated with relapse in the preoccupation/anticipation stage and then a return to the binge/intoxication stage. Hyperkatifeia can also drive the malaise of protracted abstinence that sets up a return to the binge/intoxication stage via craving and relapse in the preoccupation/anticipation stage. (Figure modified from Koob GF, Arends MA, Le Moal M: Drugs, Addiction, and the Brain. San Diego, Academic Press, 2014.)For many years, positive reinforcement was postulated to be the driving motivational construct in addiction. Substantial work focused on neural circuits that are engaged in the positive hedonic effects of drugs. However, a growing body of evidence also implicates negative reinforcement in driving and maintaining addiction. Negative reinforcement can be defined as an increase in the probability of a response that is produced by the removal of an aversive event. In the context of addiction, negative reinforcement can initially draw an individual into unhealthy patterns of substance use by reducing existing discomfort and, as addiction develops, may subsequently manifest in continuing substance use in an effort to reduce, terminate, or prevent the negative experience of drug withdrawal.Hyperkatifeia and Negative ReinforcementThe term withdrawal can be defined simply as abstinence from, or the removal of, chronic drug use, usually characterized by signs and symptoms that are opposite to the acute positively perceived effects of the drug (7). Withdrawal from drugs of abuse is one of 11 criteria that are used to diagnose substance use disorder in DSM-5 and one of six criteria that are used to diagnose substance dependence in ICD-10 (8). Historically, and still embedded in current thinking about addiction, withdrawal is inextricably linked to physical or somatic signs (9). For many drugs, however, including alcohol, the key components of withdrawal that motivate further use are such symptoms as anxiety, dysphoria, pain, irritability, sleep disturbances, and general malaise. Although some of these symptoms can be linked directly to physical disturbances, such as gastrointestinal distress, most of them involve changes in brain reward and stress systems (10–13). The emergence of negative emotional symptoms following repeated substance use has a theoretical basis in opponent process theory as proposed by Solomon and Corbit (14), whereby counteradaptations occur in which the initial acute hedonic effects of a drug are opposed by homeostatic changes in systems that mediate these primary hedonic effects. As a result, with repeated drug taking, tolerance develops to the hedonic effects, and a greater amount and more frequent use of the previously rewarding drug are needed to maintain or approach euthymia.Expanding this concept beyond adaptations that counteract the initial rewarding effects of a drug, others have argued that the opponent process that underlies withdrawal involves the recruitment of brain stress systems (11, 15). Alcohol and other substances can initially dampen stress-related brain function and reduce emotional discomfort, but the resulting neuroadaptations subsequently lead to the need for escalating doses and the emergence of an augmented state of emotional discomfort when the drug wears off. To capture the essence of the negative emotional state that is associated with drug withdrawal, the term hyperkatifeia was introduced. Hyperkatifeia (derived from the Greek katifeia for dejection or negative emotional state) is defined as an increase in intensity of the constellation of negative emotional or motivational signs and symptoms of withdrawal from drugs of abuse (16). This overactive negative emotional state is also hypothesized to sensitize with repeated drug exposure and withdrawal and drive an increase in the role of negative reinforcement in maintaining substance use as addiction develops (17).Validation of the Negative Emotional State Domain in Alcohol Use DisorderAdvances in the social psychology of self-regulation, neurobiological advances, and imaging studies led to the framework of the three domains that are outlined above—executive function, incentive salience, and negative emotionality—each linked to different phases of the addiction cycle. One extrapolation of this work is that these elements form the core functional elements of AUD and as such provide new neuroclinical measures, termed the Addictions Neuroclinical Assessment (ANA), to differentiate patients who meet clinical criteria for addiction for the same agent while differing in etiology, prognosis, and treatment response (18). As a result, this framework could lead to a better understanding of the mechanisms that provoke and maintain addiction. Indeed, a study evaluated the utility of the ANA for translation to a clinical framework and showed that the three neurofunctional domains were validated using a factor analysis of a deeply phenotyped clinical sample (19). Subsequent studies analyzed the ANA approach specifically for the negative emotionality domain in a treatment-seeking AUD sample and showed that a one-factor model was an excellent fit for all assessments in this domain. This negative emotionality domain was time and sex invariant and was associated with drinking patterns and reasons to drink (20). Another study, using a multilevel growth model analysis of data from the Prospective Study sample of the Collaborative Study on the Genetics of Alcoholism, found that positive reinforcement that was associated with alcohol consumption did not differ as a function of alcohol dependence, but negative reinforcement that was associated with alcohol consumption became stronger as alcohol dependence developed (21).Collectively, these results suggest that in AUD, the negative emotionality domain, reflecting symptoms that are associated with hyperkatifeia, plays an important role in the addiction cycle, a role at least equal to that of incentive salience, pathological habits, and craving. Although hyperkatifeia is most likely to manifest during the withdrawal/negative affect stage, it can also infiltrate other stages of the addiction cycle to promote or facilitate impulsivity (negative urgency), craving, and relapse (Figure 1).Negative Urgency, Protracted Abstinence, and RelapseClassically, individuals with AUD may start with recreational use of the drug during the binge/intoxication stage and progress to the withdrawal/negative affect stage as negative reinforcement evolves and impaired functioning of the frontal cortex progresses, facilitating reemergence of a binge despite aversive consequences (Figure 1). However, our hypothesis is that a significant amount of alcohol misuse develops because negative emotional states from other sources can drive alcohol seeking and use and may be an initial starting point for entering the addiction cycle via self-medication (22) (Figure 1). Thus, we suggest that entrance into the three-stage cycle at any stage can engage neuroadaptations that lead to hyperkatifeia; conversely, hyperkatifeia can contribute to all three stages of the addiction cycle (Figure 1).Negative UrgencyNegative urgency is an emotion-based trait that is characterized by a tendency to act rashly and impulsively when experiencing unusually strong negative emotions (23, 24). The trait is associated with a higher likelihood of problematic risk taking, including the early initiation and escalation of alcohol and other drug use (25, 26), and an increase in alcohol consumption in response to negative mood (27–29). Negative urgency may be an early risk factor for substance use disorders and has been hypothesized to be an endophenotype for alcohol and tobacco addiction (23, 27). The negative emotional symptoms that are associated with hyperkatifeia and the withdrawal/negative affect stage may elicit intense urges that are moderated or mediated by negative urgency (24). Additionally, impairments in executive control that are associated with negative urgency may decrease the capacity to resist urges to pursue substance use in the preoccupation/anticipation stage, such that an episode of use occurs rapidly and without forethought of potential harm despite actual consequences (19, 24) (Figure 1).Protracted AbstinenceWithdrawal symptoms can persist past the acute withdrawal phase that follows the binge/intoxication stage and continue through the preoccupation/anticipation stage (30). By one estimate, 75% of people who experience alcohol withdrawal have symptoms that endure beyond the acute withdrawal phase (31, 32). This extended period is termed protracted abstinence or protracted withdrawal and begins approximately 1 week after the resolution of physical withdrawal signs. For patients with AUD who experience protracted withdrawal, such symptoms as hypohedonia, anxiety, and sleep disturbances typically abate within 3–6 weeks but can persist for longer periods in a more subtle form. These subtle changes in affective processing could be sufficient to lead to craving and relapse under stressful circumstances (30, 33). Human laboratory studies and clinical trials demonstrate the strength of this interaction and suggest that cue reactivity, combined with a negative emotional overlay, can predict the efficacy of medications for treating AUD (34–36).RelapseIn the preoccupation/anticipation (craving) stage, both environmental factors and internal states are hypothesized to contribute to relapse (6). External factors include priming doses of the drug, drug-associated cues, and exposure to stressors. Internal factors include malaise, a state of stress, or interoceptive cues, many of which can be subsumed under the hyperkatifeia construct (see above).Stress is a major determinant of relapse and vulnerability to relapse in individuals with AUD (3, 4, 37–39). Exposure to negative affect, stress, or withdrawal-related distress also increases alcohol craving (34, 40, 41). For example, in a prospective study of patients with AUD who were enrolled in a 12-week outpatient study, high stress-induced craving was associated with a significantly shorter time to alcohol relapse, a higher mean number of drinks per week, a lower percentage of days abstinent, and lower rates of complete abstinence over the study duration (40). These results suggested that stress-related increases in alcohol craving are associated with poorer alcohol treatment outcomes, supporting the use of stress-induced craving as a predictor of alcohol relapse propensity (40).Neurobiology of HyperkatifeiaHyperkatifeia has been hypothesized to be mediated by profound changes in the brain reward and stress systems, providing a basis of an additional source of motivation for alcohol misuse via negative reinforcement (7). As tolerance and withdrawal develop, reward function decreases and is mediated by acute losses of function of dopamine, serotonin, and endogenous opioid systems and neuroadaptations in the γ-aminobutyric acid/glutamate systems (7). Such a hypohedonia component of hyperkatifeia has been termed a within-system neuroadaptation to excessive alcohol intake, in which alcohol reward circuits are compromised (6, 10).Perhaps even more compelling for the development and persistence of hyperkatifeia are between-system neuroadaptations (6, 10). Brain stress systems, such as corticotropin-releasing factor, glucocorticoids, norepinephrine, dynorphin, vasopressin, hypocretin, and substance P, and neuroimmune systems are recruited by excessive alcohol consumption, producing aversive or stress-like states, also contributing to hyperkatifeia (7). There is also evidence that deficits in stress-buffering systems, such as neuropeptide Y, nociceptin, endocannabinoids, and oxytocin, may also contribute to hyperkatifeia (7). Molecular mechanisms that are involved in the withdrawal/negative affect stage can contribute to molecular loading on within- and between-system neurocircuit adaptations (42). Many of these neurochemical neuroadaptations continue into protracted abstinence and parallel neurochemical neuroadaptations that are associated with acute withdrawal (7).Hyperkatifeia, Deaths of Despair, and Implications for the COVID-19 PandemicDeaths of DespairAfter increasing for decades, life expectancy in the United States began to decline around 2014. The decline was driven in part by what Case and Deaton (43, 44) referred to as "deaths of despair"—deaths from drug and alcohol overdoses, liver disease, and suicide. These deaths are linked to declining quality of life, including declines in emotional and physical well-being, financial difficulties, and serious mental illness. Increases in deaths of despair began in the late 1990s among non-Hispanic white men and women in midlife (43, 45). However, such deaths are now increasing among people in midlife across racial and ethnic groups (46–48).As discussed previously, alcohol can temporarily dampen negative emotional states, providing short-term relief and powerful reinforcement for continued use. Over time, neuroadaptations reduce the relief that is provided by alcohol and increase emotional misery between episodes of use. Alcohol plays a prominent role in deaths of despair and contributes to an estimated 15% of all drug overdoses (49, 50), 26% of suicides (51), and 50% of deaths from liver diseases (52). Deaths in the United States that involve alcohol are increasing, having doubled from 1999 to 2017 (53, 54), as are rates of alcohol-related emergency department visits and hospitalizations.Alcohol Consumption During the Pandemic: Disinhibition and DiseaseThe COVID-19 pandemic can be considered a major stressful event that affects daily life for people throughout most of the world. Mental health experts fear that the stress, uncertainty, and trauma of the pandemic could precipitate a mental health crisis in the United States and elsewhere (55). Alcohol use could escalate during the pandemic, leading to a greater treatment need and a greater burden of alcohol on public health. Combining available data on alcohol sales, including both on-premise (e.g., bars and restaurants) and off-premise (e.g., liquor and grocery stores) locations, during the pandemic suggests that sales increased roughly 5% overall in March 2020 but returned to near pre-pandemic levels in May 2020 (56). Sales data do not indicate whether some people are drinking more. A recent survey by the Research Triangle Institute found that roughly 40% of respondents reported an increase in alcohol use during the pandemic, whereas 30% reported a decrease (57). Another survey suggested that greater COVID-related distress was associated with larger increases in alcohol use (58).Coping With Stress: Psychosocial Side Effects of COVID-19Physical distancing during the pandemic has also restricted social interaction. Given that social interaction is a powerful reinforcer for humans, the lack of it can contribute to loneliness, dysphoria, depression, and malaise. As a result, social isolation could serve as a source of stress that motivates drinking to cope. Using alcohol to dampen emotional misery is a form of misregulation in the domain of self-regulation (59) and tends to make people more miserable once the alcohol wears off and motivated to drink again to fix a problem that is now caused or exacerbated by alcohol itself. Drinking to cope with negative emotions places an individual at a higher risk of developing AUD (60, 61). Therefore, alcohol drinking is not a safe or sustainable solution for the emotional strain that many people are experiencing during the pandemic.The physical distancing that has been imposed during the pandemic may be particularly challenging for people who are in recovery from AUD. As noted above, stress and negative affect are major triggers of relapse (1–4). Although there are options for one-on-one sessions through telehealth or participation in online mutual support groups (https://www.niaaa.nih.gov/alcohol-and-covid-19; https://alcoholtreatment.niaaa.nih.gov), face-to-face therapy sessions and in-person mutual support group meetings that are often critical for successful treatment and recovery are unavailable to most people right now, highlighting a current challenge to treatment.Alcohol is a well-known social lubricant and decreases inhibitions in interactions with both friends and strangers (62, 63). It also impairs decision making, threat detection, and impulse control, which could have an impact on adherence to guidelines on physical distancing and mask wearing, potentially increasing spread of the SARS-CoV-2 virus that causes COVID-19. In addition to potentially increasing viral transmission, there are reasons to suspect that excessive alcohol use can increase the risk of infection with SARS-CoV-2 and decrease the body's defense system via mechanisms that are similar to the interaction between alcohol and acute respiratory distress syndrome (64, 65).ConclusionsUsing AUD as a prototype, we argue that negative emotional states play an often overlooked but key role throughout the addiction cycle. In some cases, the misuse of alcohol is an attempt to mitigate misery and as such provides entry into the addiction cycle. For other individuals who are already experiencing AUD, the hyperkatifeia of alcohol and other drug withdrawal extends long past the acute physical (often somatic) manifestations of withdrawal and perpetuates AUD. Such negative emotional states in addiction fit an allostatic view, manifested as a break with normal reward and stress regulation (66). Allostasis is defined as an attempt to maintain hedonic stability through change. The loss of reward function, gain of stress system function, and loss of executive control progressively produce an allostatic load that manifests as an allostatic state (i.e., the hyperkatifeia of acute and protracted withdrawal). These changes can ultimately lead to the pathological state of addiction. The ongoing COVID-19 pandemic has resulted in social isolation, the loss of loved ones, the loss of livelihood, and drinking to cope, thereby exacerbating negative emotional states for many. The fear, dysphoria, and social isolation of COVID-19 could greatly augment allostatic load in the domain of addiction. Because the pandemic began against the backdrop of increases in deaths of despair in the United States, it is possible that increases in pandemic-related stress combined with elevated substance use could fuel an increase in mortality from overdoses, suicide, and alcohol-related liver disease. The pandemic challenges us to develop new ways to meet the expanding needs of the etiology, diagnosis, prevention, and treatment of addiction and avert a looming crisis in the addiction field.National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md. (all authors); National Institute on Drug Abuse, Bethesda, Md. (Koob).Send correspondence to Dr. Koob ([email protected]).Dr. Powell holds stock in Pfizer, Inc. 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