2. COVID-19 Pandemic and Mental Health

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significant rise in addictions and related mental illnesses;

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significant rise in the corresponding anti-depressant prescription uptake;

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increased risk of suicidal ideation or suicide.

Any potential doubts about the impact of COVID-19 on mental health have been largely put to rest by the most recent papers on the topic ^{[8][9][10][11][12]}[90,91,92,93,94]. Loneliness, physical exhaustion, sleep disturbances, and anhedonia linked to compulsive or addictive behaviors such as binge-eating ^[13][14][95,96], substance abuse ^[15][97], and digital reward craving ^[16][98] were identified asbeing linked to suicidal ideation ^[13][17][18][95,99,100]—in particular, in younger individuals—during and after the pandemic. These reflect some of the most negative effects of pandemic-related adversity on mental health worldwide.

2.1. Adversity and Vulnerability

Mental health issues arise from a specific context. Recently reported effects of the pandemic have shown, beyond all reasonable doubt, that adversity affects people’s capacity tocope with the stresses it produces. Conditions of extreme adversity challenge the stress and immune system responses needed for coping, and beyond a certain threshold, such conditions can trigger behavioral changes as listed and discussed here above; all of them have been functionally linked to the complex brain pathways involving dopamine release, reward mechanisms, and their interactions or regulations ^[19][20][77,79]. During the different waves of the pandemic, many individuals had an actual COVID-19 infection, with direct effects on the brain’s immune system, stress centers, and the dopamine system, affecting people’s mood beyond the actual duration of the illness. Cohort studies examining the psychopathological and cognitive status of COVID-19 pneumonia survivors ^[21][101], for example, have shown that three months after discharge from the hospital, close to 40% still self-rated their symptoms in the clinical range for at least one psychopathological dimension, with persistent depressive symptomatology, while anxiety and insomnia progressively decreased during follow-up. Studies on the impact of the COVID-19 pandemic on individuals with eating disorders have been performed all over the world, showing that the traumatic effects of COVID-19 have exacerbated specific eating disorder-related psychopathologies ^[22][102], pointing towards complex interactions between environmental and personal factors. Healthy siblings of patients with eating disorders have beenfound to present specific psychological vulnerabilities, i.e., specific associations between interpersonal sensitivity and posttraumatic symptoms, including anxiety, depression, and compulsive behaviors ^[22][23][102,103]. Moreover, having to cope with adversity during childhood increases the risk of mental health problems in adulthood, and it has been suggested that this effect may be mediated by increased striatal dopamine neurotransmission ^[24][104]. Also, while resilience may be viewed as an individual’s positive adaptation to experiences of adversity ^[25][105], it is also known that conditions of adversity reinforce the already exisiting vulnerability to mental illness and may create a new vulnerabilty duringspecific adverse contexts such as a pandemic ^[10][92] or armed conflict ^[26][106]. It has been confirmed that stress responses can cause functional changes in the amygdala and the dopaminergic circuits of the brain in relation to stress-induced cortisol release mechanisms ^[26][27][28][106,107,108]. Some of these studies have shown a cortisol-induced increase in serotonin in subjects with major depressive disorder, offering further insight into the functional links between stress, sleep disorders, and depression, where an increase in one brain correlate affects another, thereby creating or increasing the physiological vulnerability to mental illness in individuals under prolonged stress.

2.2. Bingeing

The COVID-19 pandemic creatednegative health consequences such as consuming high-fat and sugar foods, increasing body weight ^[29][109], anxiety and depression ^[30][110], anhedonia ^[30][31][110,111], or a combination thereof ^[32][83]. As a core characteristic of eating disorders and all forms of addiction ^[33][22], bingeing is associated with changes in the activity of the brain’s reward system in the process of pathological adaptation of the central nervous system through deregulation of the reward mechanisms generating positive reinforcement. As explained earlier, this deregulation progressively leads to the consolidation of the anti-reward brain state that produces anxiety, anhedonia, and depression. Most people during COVID-19 lockdown reportedly turned to substances or other “rewarding” activities to deal with the stress of isolation and the negative feelings it engendered ^[34][35][112,113]. A number of factors related to the COVID-19 pandemic may have contributed to the reportedly high incidence of food addictions during and after that period ^[35][36][113,114]. It has been suggested that people under the influence of the excessive and uncontrolled consumption of extremely palatable foods experience similar highreward sensations as recorded for addicts resorting to classic intoxicants, both at the behavioral and neurobiological levels ^[35][36][37][88,113,114]. As lives and daily routines were transformed by the pandemic and rapidly rising anxiety fueled by social isolation and, often, unemployment, the mental health of millions is at stake. In the United States alone ^[38][115], close to 60% of adults screened declared that the pandemic led them to abuse alcohol and other drugs, binge eating, and/or compulsive internet gambling.

2.3. The New Digital Drug

COVID-19 spread across the world ata rapid pace, and to further limit the spread of infection, lockdowns were declared in most parts of the world. People were forced to stay indoors, and the internet was the only source of entertainment. This context engendered addictive behavior with measurable negative effects on anxiety and sleep quality, especially among younger individuals ^{[38][39][40][41]}[115,116,117,118]. Digital addiction involves theinternet as a channel through which individuals may access whatever content they want (games, social media, shopping, etc.) wherever and whenever they want. The development of the addictive response is digitally facilitated by such instant availability ^{[40][41][42][43][44][45]}[117,118,119,120,121,122]. At an advanced stage, digital addiction ^[41][118] is associated with significant and permanent symptomatic psychological, cognitive, and physiological states, with a measurable dopamine deficiency and impaired mental health ^[44][121]. Psychological stress ^{[44][45][46][47]}[121,122,123,124], anxiety and depression ^[48][49][50][125,126,127], eating disorders ^[51][52][53][128,129,130], sleeplessness ^[54][55][131,132], and mood changes, along with suicidal ideation ^[56][57][133,134], are the most frequently reported. A compilation of cross-national studies on more than 89,000 participants from 31 nations performed almost ten years ago, well before the COVID-19 pandemic, already suggested a global prevalence estimate for digital addiction of 6% worldwide ^[43][120]. Interdependent variables such as sociocultural factors, biological vulnerabilities (genetic predisposition and preexisting metabolic disorders), and psychological factors (personality characteristics and a negative affect) play a critical role ^{[58][59][60][61][62][63]}[135,136,137,138,139,140]. Excessive seeking of the new digital drug and addiction to the internet have been identified as part of the consequences of the COVID-19 pandemic, with a major impact on the mental health of predominantly young people and teenagers ^{[61][62][63][64][65][66][67][68][69]}[138,139,140,141,142,143,144,145,146]. This involves, like all compulsive behavior loops, the brain’s reward circuitry, with all the complex interactions between environmental, metabolic, and neurobiological changes in the brain discussed above. Dopamine, and the modulation thereof under conditions of adversity and stress (Figure 1), is the common functional denominator ^[70][147].

Figure 1. Behavioral consequences of an anti-reward brain state, with ultimately depleted dopamine levels in the reward centersand increased cortisol levels in the centers that regulate the brain’s response in pathological adaptation to chronic stress. Under adverse environmental conditions, such as those generated by the COVID-19 pandemic, healthy reward-seeking has progressively evolved into stress-related compulsory behaviors and/or addictions leading to anhedonia and related mental health issues worldwide.