An Integrated Immuno-Reward Model of Adolescent Depression: Theory, Evidence, and Implications

Abstract

Adolescence is an “age of risk” for the emergence of depression. Despite its prevalence and public health significance, there are major unanswered questions regarding the mechanisms contributing to depression’s etiology and surge in adolescence. Separate lines of research have investigated the roles of inflammation and low reward responsiveness in depression and recent evidence suggests bidirectional associations between inflammation and reward responsiveness. In this article, we review this evidence, present an integrated immuno-reward model of adolescent depression, specifically, motivational and somatic symptoms of depression, and discuss the role of stress and early adversity in amplifying immune-reward interactions. We end with implications of the immuno-reward model for future research, early identification of at-risk adolescents, intervention, and public health policy.

Adolescence is characterized by large changes in brain, immunological, cognitive, emotional, and social development. It also is an “age of risk” for increases in symptoms of depression and first onset of major depressive disorder (MDD; Alloy et al., 2023). Depression, in turn, is a major public health concern because it is prevalent, recurrent, and associated with much functional impairment, increased suicide risk, and high personal and societal costs (Nusslock et al., 2024). Depressed teens’ impairment not only wreaks havoc in their lives during adolescence, but also limits their opportunities in adulthood. Why are adolescents vulnerable to the onset of depression? Understanding risk factors that may contribute to the causes of depression is crucial for translating basic research to interventions that can prevent or treat the “epidemic” of depression during the vulnerable period of adolescence.

The functioning of neurobiological systems provides a way to understand associations between environmental experiences, behaviors, and various symptoms of psychopathology. We hypothesize that two such systems, the immune system and the reward system experience important developments during adolescence and interact to increase risk for particular depression symptoms during this period (Alloy et al., 2023; Nusslock et al., 2024). Although we present an immuno-reward model of adolescent depression, most literature that forms the evidence base for this model was conducted in adults. Thus, many of our citations are to adult studies, but we include relevant studies of adolescents when possible. In addition, we also recognize the importance to depression of interactions between the immune system and the brain’s threat circuitry and prefrontal cortex (PFC) executive functioning (Nusslock & Miller, 2016; Nusslock et al., 2024). However, this paper focuses on unpacking the immuno-reward pathway particularly relevant to the development of anhedonia (low interest in or pleasure from rewards) and somatic components of depression in adolescence. The immuno-threat and immuno-executive function pathways have different developmental peak maturation periods (earlier childhood for immuno-threat and young adulthood for immuno-PFC; Nusslock et al., 2024) that make them less relevant to the surge in depression that occurs in adolescence specifically.

THE ROLE OF INFLAMMATION IN DEPRESSION

Research over the past two decades suggests that chronic inflammation contributes to risk for depression (Figure 1, light green inflammation vulnerability box). The immune system responds via inflammation to injury and infection and works to promote tissue healing and destroy invading disease-causing microbes (pathogens; e.g., bacteria, viruses). Inflammation starts when circulating immune cells detect damaged tissue or invasion by pathogens and release communication molecules called inflammatory cytokines. Cytokines can access the brain via active transport, leaky regions of the blood-brain-barrier (BBB), or via the afferent vagal nerve, and directly modulate brain structure and function (Nusslock et al., 2024). These cytokines coordinate the immune system response that usually leads to tissue repair and pathogen removal, subsequently leading the inflammation to subside (Nusslock et al., 2024). However, if the immune system is dysregulated due to chronic stress, chronic disease, or other factors (e.g., toxin exposure, autoimmune illness) and cannot dampen the inflammation, a chronic, low-grade inflammation may develop, which, in turn, can increase risk for some symptoms of depression.

Figure 1.

Integrated Immuno-Reward Model of Adolescent Depression.

Note. Trait-like vulnerabilities and current levels of similar constructs are represented by boxes with lighter and darker shades of the same color, respectively. In the model, exposure to early adversity contributes to the development of both chronic low-grade inflammation and low reward responsiveness separately (light orange arrows) and enhances the bidirectional relationship between the immune and reward systems (bidirectional green arrow). Low reward responsiveness both interacts with the experience of recent reward system deactivating events to lead to excessive decreases in approach motivation (gray diagonal arrow from reward vulnerability box to dark orange arrow from current stress box to current reward state box) and increases exposure to these reward-deactivating events via stress generation processes (gray stress generation arrow). Recent stressors, particularly reward-deactivating events, contribute to heightened current inflammation (dark orange arrow from current stress box to current inflammation box). Low trait reward responsiveness also contributes to heightened current inflammation via inflammation enhancing behaviors (e.g., substance use, poor diet and sleep; gray inflammation enhancing behaviors arrow). Heightened inflammation also contributes to excessive decrease in approach motivation (green arrow from current inflammation box to current reward state box). Finally, excessive decrease in approach motivation leads to depressive symptoms or episodes, particularly anhedonia and somatic symptoms.

Adapted from Alloy, L.B., Chat, I.K.-Y., Grehl, M.M., Stephenson, A.R., Adogli, Z.V., Olino, T.M., Ellman, L.M., Miller, G.E., & Nusslock, R. (2023). Reward and Immune Systems in Emotion (RISE) prospective longitudinal study: Protocol overview of an integrative reward-inflammation model of first onset of major depression in adolescence. Brain, Behavior, and Immunity: Health, 30, 100643

The immune system reacts to psychological as well as physical threats. Experience of stressful life events often leads to increased inflammation (dark orange arrow from current stress box to current inflammation box in Figure 1) and chronic stress exposure has been related to persistent, low-grade inflammation (light orange arrow from stress vulnerability box to inflammation vulnerability box in Figure 1; Chiang et al., 2022; Kautz et al., 2023). Moreover, acute and chronic stress are major risk factors for depression. During adolescence, exposure to stressful events and sensitivity to these stressors increases (Kautz et al., 2020). Further, normative developmental changes in immune function and BBB permeability occur (Brenhouse & Schwarz, 2016; Simon et al., 2015) in adolescence that may be facilitated by pubertal increases in estrogens and androgens that modulate the peripheral immune system (Brenhouse & Schwarz, 2016). These developmental changes may cause the immune system to be especially sensitive to stress and adversity during adolescence (Lam et al., 2021), increasing risk for chronic low-grade inflammation in adolescence (Brenhouse & Schwarz, 2016) and depression.

Evidence for Inflammation as a Risk for Depression

An early impetus for inflammation models of depression was the observation that the “sickness syndrome” (fatigue, inactivity, poor appetite, anhedonia) that results from elevated inflammation resembles symptoms of depression (e.g., Irwin & Miller, 2007). In addition, depression often co-occurs with medical conditions that involve inflammation (e.g., heart disease, autoimmune disorders; Nusslock et al., 2024). Meta-analyses have found that depressed individuals exhibit higher peripheral inflammatory cytokines, particularly interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), and the acute phase inflammatory protein, c-reactive protein (CRP), than controls (e.g., Osimo et al., 2019). Similarly, other studies have reported elevated inflammatory biomarkers in the cerebrospinal fluid and brain tissue of depressed individuals relative to non-psychiatric controls (Felger et al., 2020). These cross-sectional findings are bolstered by meta-analytic evidence that elevated inflammatory biomarkers, particularly IL-6 and CRP, predict depression onset prospectively, suggesting that inflammation may be a risk factor for depression and not just a consequence of depression (Mac Giollabhui et al., 2021; Osimo et al., 2019).

Studies that directly manipulate inflammatory stimuli further suggest a potential causal role for inflammation in some depressions. Administration of the pro-inflammatory cytokine interferon-alpha to help treat some cancers and infectious diseases leads to development of symptoms of anhedonia, motor slowing, fatigue and full-blown MDD in 30–50% of patients, depending on the dose (Capuron et al., 2009). Similar but milder symptoms occur in healthy individuals who are administered mild inflammatory stimuli such as typhoid vaccine or low-dose endotoxins (Moieni et al., 2019). Conversely, blocking inflammation with anti-cytokine therapies reduces depression in patients with autoimmune and inflammatory disorders and in otherwise medically healthy individuals with MDD and elevated inflammation (Wittenberg et al., 2020).

Inflammation and Specific Symptoms of Depression

Although meta-analyses support a role of inflammation in depression, only about 30% of depressed individuals exhibit elevated inflammation (Osimo et al., 2019). Given that depression is heterogeneous, this finding implies that inflammation may provide risk for only some subgroups of depressed individuals, namely those with a symptom profile involving anhedonia and vegetative/somatic (e.g., fatigue, poor appetite, motor slowing) symptoms (Dooley et al., 2018). Indeed, animal and human research suggests that inflammation may be particularly associated with anhedonia and motivational deficits (Lucido et al., 2021), suggesting potential interactions with the brain’s reward circuitry that underlies motivation and reward processing (light green bidirectional arrow between inflammation vulnerability box and reward vulnerability box and dark green arrow from current inflammation box to current reward state box in Figure 1). These findings of particular relationships between inflammation and motivational and somatic symptoms fits with a growing recognition of the importance of studying specific pathways that may lead to specific symptoms rather than broad categories like depression.

The Role of Life Stress in the Inflammation – Depression Association

Exposure to stressful life events also leads to increased inflammation (Slavich & Irwin, 2014). Normatively, adolescence is characterized by increased stress, particularly social and interpersonal stressors, and failures, losses, and rejections in the interpersonal domain are particularly likely to precipitate depressive symptoms (Slavich & Irwin, 2014). Accumulation of negative interpersonal daily stressors and higher levels of peer victimization during adolescence predict elevated cytokine levels following a laboratory stress test in adolescents, and stressful events from birth to age 8 predict elevated CRP levels at age 15 (see Kautz et al., 2020 for review). In addition, community adolescents who experienced both recent stressful events and larger increases in inflammatory activity following these stressors exhibited more severe depressive symptoms a year later (Kautz et al., 2020).

Moreover, the link between inflammation and depression in adolescence and adulthood is strengthened by prior exposure to adversity during childhood. Childhood adversity (e.g., poverty, early deprivation, parental maltreatment) is hypothesized to sensitize children’s immune cells and program them to mount exaggerated cytokine responses to infection, injuries, and subsequent stressors and to desensitize them to anti-inflammatory cytokines and glucocorticoids like cortisol that normally inhibit inflammatory responses (Miller et al., 2011). As such, childhood adversity may dysregulate the immune system and is associated with chronic low-grade inflammation that persists and even worsens in adolescence and adulthood (light orange arrow from the stress vulnerability box to the inflammation box in Figure 1; Chiang et al., 2022; Kautz et al., 2023). Evidence supports enhanced inflammation-depression associations in individuals exposed to childhood adversity (Alloy et al., 2023). And, stressors during adolescence as well as pubertal development can further strengthen the link between early adversity and inflammation (Nusslock et al., 2024).

THE ROLE OF BLUNTED REWARD RESPONSIVENESS IN DEPRESSION

The immune system communicates with the brain’s reward system in a bidirectional fashion (light green bidirectional arrow between the inflammation vulnerability and reward vulnerability boxes in Figure 1; Alloy et al., 2023; Felger & Treadway, 2017; Nusslock et al., 2024). The reward system has been linked to a corticostriatal circuit, involving the ventral striatum (VS) and orbitofrontal cortex (OFC), among other brain structures. This circuit, which involves dopamine and the opioids, as well as other neurotransmission systems, regulates goal-directed behavior and approach motivation and responds to the anticipation and receipt of rewards. Monetary and social rewards share a “common neural currency”, with both reward types activating common regions (VS, OFC) in the corticostriatal reward circuit (Gu et al., 2019). In early adolescence, this circuit begins to undergo rapid development, resulting in normative increases in motivation for and responsiveness to rewards (see Alloy et al., 2016; Nusslock & Alloy, 2017 for reviews). Dopamine transmission also increases in adolescence (Wahlstrom et al., 2010). These adolescent developments may contribute to increased sensitivity of the brain’s reward system during adolescence and the increased risk for depression during this period. Activation of the reward system by internal (e.g., expectancy of promotion) or external (e.g., winning a prize) reward-relevant events leads to increased goal-related thoughts, incentive motivation, and motor behavior directed toward attaining rewards, as well as positive emotions such as hope and happiness, or to anger when goal-striving is blocked. Deactivation of the reward system, in turn, by events such as losses and failures that cannot be changed (dark orange arrow from the current stress box to the current reward state box in Figure 1), leads to decreased goal-related cognitions and motivation, increased withdrawal, anhedonia, and sadness (Alloy et al., 2016; Nusslock & Alloy, 2017).

Evidence for Blunted Reward Responsiveness as a Risk for Depression

Decreased positive emotions and reduced sensitivity to rewards (anhedonia) are core features of depression. According to reward hyposensitivity models of depression, individuals with a trait-like hyposensitivity to rewards are vulnerable to depression, both because their reward systems deactivate more strongly when they experience unchangeable failures and losses (gray diagonal arrow from the reward vulnerability box to the dark orange arrow between the current stress box and current reward state box indicating a reward vulnerability x reward-deactivation events interaction in Figure 1) and because they are less likely to pursue rewards in the first place (light gray stress generation arrow in Figure 1; Alloy et al., 2016; Nusslock & Alloy, 2017). Consistent with these models, individuals with depression exhibit less responsiveness to rewards on self-report questionnaires and behavioral tasks of reward learning, decision-making, and pursuit than non-depressed persons. fMRI studies have found hypo-responsiveness to reward in the VS, but hyper-responsiveness in the OFC among depressed individuals compared to controls, suggesting that dysregulated corticostriatal connectivity may be involved in reward-processing abnormalities in depression (Ng et al., 2019). Individuals with a depression history but currently in remission and nondepressed offspring of depressed parents at heightened risk for depression also exhibit lower reward sensitivity on questionnaires, behavioral tasks, and lower striatal activation to rewards (Alloy et al., 2016; Nusslock & Alloy, 2017). The strongest evidence that blunted reward responsiveness is a vulnerability for depression comes from prospective studies that find that lower reward responsiveness measured by questionnaires, behavioral tasks, EEG, and VS activation to rewards, including in adolescents, predict future depression (e.g., Stringaris et al., 2015; Telzer et al., 2014).

The Role of Life Stress in Reward Responsiveness

Both early adversity and recent stressors influence reward responsiveness. Development of the brain’s corticostriatal reward circuit and reward processing deficits on behavioral and neural reward tasks are affected by adversity (e.g., abuse, deprivation) in childhood and adolescence (light orange arrow from the stress vulnerability box to the reward vulnerability box in Figure 1; Alloy et al., 2023; Nusslock et al., 2024). Adversity-exposed adolescents don’t display the typical increase in reward sensitivity during this time period and are more likely to become depressed (Duffy et al., 2018; Goff et al., 2013). Further, exposure to recent stressors, including life events that tend to activate (goal-striving or goal-attainment events) or deactivate (unmodifiable failures or losses) the reward system, modulates neural reward processing (Chat et al., 2022).

AN INTEGRATED IMMUNO-REWARD MODEL OF ADOLESCENT DEPRESSION

Based on evidence that the immune and reward systems are bidirectionally associated and influence each other, we and others (Alloy et al., 2023; Felger & Treadway, 2017; Nusslock et al., 2024; Slavich & Irwin, 2014) have proposed integrated immuno-reward models of depression that can be applied to the rise in risk for depression in adolescence. Peripheral inflammatory proteins access the brain and can lower reward responsiveness to many types of rewards (but see Eisenberger et al., 2017 and Muscatell & Inagaki, 2021 for evidence that inflammation may enhance neural sensitivity to some social rewards). When regulated, the lower reward responsiveness is adaptive because it leads to behaviors (e.g., inactivity) that divert resources to the immune system to facilitate wound healing and pathogen removal. However, when dysregulated, inflammation can produce chronic blunted reward responsiveness (light green arrow from the inflammation vulnerability box to the reward vulnerability box in Figure 1), reflected in anhedonia and low mood. This blunted reward function may then initiate unhealthy, self-medicating behaviors (poor diet and sleep, substance use) to cope with the anhedonia and dysphoria, which further increase inflammation (gray inflammation enhancing behaviors arrow from the reward vulnerability box to the current inflammation box in Figure 1). These behaviors also tend to increase in adolescence (Kuhlman et al., 2017). Thus, over time, dysregulation in each system exacerbates dysregulation in the other, leading to a synergistic, two-pronged vulnerability for depression. Moreover, not only does exposure to early adversity and recent stressors influence the developing immune and reward systems separately, adversity exposure also enhances the connection between inflammation and reward responsiveness (Miller et al., 2024) and may set the stage for immune-reward dysregulation in adolescent depression.

Inflammation to Blunted Reward Responsiveness Pathway

Peripheral inflammatory proteins can stimulate the additional production of pro-inflammatory cytokines in brain tissue by microglia, the central nervous system’s primary innate immune cell (Nusslock et al., 2024). The corticostriatal reward circuit is a primary target of such activated brain cytokines (Lucido et al., 2021). Brain inflammation can reduce reward responsiveness by modulating the synthesis, release, and reuptake of glutamate and dopamine in the corticostriatal circuit (Nusslock et al., 2024). Individuals exposed to pro-inflammatory stimuli (cytokines, endotoxins, vaccines) exhibit reduced VS activity to monetary rewards. And, animals and humans with inflammation-induced reductions in striatal dopamine experience decreased motivation and a reduced willingness to pursue rewards (see Nusslock et al., 2024 for review). If this inflammation-to-reduced reward responsiveness pathway becomes chronic, it can lead to anhedonia and sustained reductions in motivation (Lucido et al., 2021), and thus, to symptoms of depression.

Reward Responsiveness to Inflammation Pathway

Reward function also can influence levels of inflammation directly or indirectly via behavior (Alloy et al., 2023; Nusslock et al., 2024). In mice, direct activation of dopaminergic neurons in the corticostriatal circuit increases immune responses in the periphery (Ben-Shaanan et al., 2016). People with low reward responsiveness often try to ameliorate their blunted reward function by engaging in pro-inflammatory behaviors, including increased substance use (Bart et al., 2021; Volkow et al., 2017), consumption of high-fat, high-sugar diets (Volkow et al., 2017), and poor sleep (Burani et al., 2021). Consistent with this view, blunted dopamine signaling in the VS is involved in drug and alcohol use, as well as food seeking and obesity (Volkow et al., 2017), and low corticostriatal activation to reward stimuli prospectively predicts substance use frequency (Bart et al., 2021). In addition, blunted reward responsiveness involving decreased response initiation may lead to neglect of normal routines (e.g., bedtime) and consequent shortened or irregular sleep (Alloy et al., 2023). Short sleep durations and experimentally-manipulated sleep deprivation, in turn, predict increases in inflammation (Irwin et al., 2016).

This bidirectional and interactive dysregulation of the immune and reward systems can increase vulnerability to depressive symptoms, particularly anhedonia and somatic symptoms, and onset of major depressive disorder. Furthermore, the increased levels of stress exposure, elevated sensitivity of the immune system to stress, rise in behaviors that enhance inflammation, and normative developments in the corticostriatal circuit that all occur during adolescence may contribute to chronic dysregulated, bidirectional inflammation-reward pathways, and thus, increased risk for depression during this developmental period.

Implications of the Immuno-Reward Model

The immuno-reward model of adolescent depression can contribute to understanding etiological pathways leading to the surge in depression that occurs in adolescence. Future research may benefit from moving away from depression as a broad, heterogenous construct to investigation of immuno-reward pathways leading to specific symptoms of motivational anhedonia and somatic features. In addition, future research should integrate the immuno-reward perspective with other neuroinflammatory pathways to create a more comprehensive model of adolescent depression (see Nusslock et al., 2024).

This model also pinpoints biobehavioral markers for identifying youth most at risk for some forms of depression who might benefit from early intervention. During regular doctors’ visits, pediatricians could screen adolescents with low-cost, quick, easily administered trait reward sensitivity measures and order assays of inflammatory markers from standard blood draws to identify vulnerable adolescents who may be candidates for early intervention.

Delineating bidirectional immune-reward pathways in the emergence of depression also could facilitate “a next generation” of behavioral and biological interventions that target immune-to-reward and reward-to-immune signaling to treat, and ideally prevent, depression (Nusslock et al., 2024). A benefit of the immuno-reward model is that it provides multiple possible points of intervention and a basis for more personalized health that targets reward or immune deficits in a subset of individuals with anhedonic depression. Some may respond better to behavioral interventions and others to biological interventions. For example, one-third of depressed individuals fail to respond to conventional antidepressant medication, and inflammation is a mechanism hypothesized to contribute to treatment resistance (Nusslock et al., 2024). Continued research on the immuno-reward model could provide the foundation for drug discovery and clinical trials of anti-inflammatory drugs (e.g., infliximab) as primary or adjunctive treatments for depression with reward neural circuits as response targets (see Miller & Raison, 2023 for pros and cons of anti-inflammatory treatments). Alternatively, transcranial magnetic stimulation (TMS), ultrasound, and temporal interference techniques that target regions of the corticostriatal circuitry may be useful in elevating reward responsiveness. Further, examining behavioral pathways of reward-immune associations can help identify modifiable targets for behavioral interventions for depression. These approaches could include sleep improvement strategies, such as regularizing bedtimes and wake times and decreasing nighttime exposure to blue light emitting screens, and promotion of low-fat, low-sugar diets. Both sleep and dietary interventions indirectly may improve chronic inflammation. Behavioral activation therapies designed to increase reward responsiveness also may prove effective.

Finally, the immuno-reward model has health policy implications in that early adversity (e.g., poverty, deprivation, trauma) strengthens inflammation-reward associations and risk for depression, and behaviors motivated to counteract blunted reward responsiveness, such as consumption of substances and poor diets, enhance inflammation. Thus, policies aimed at reducing adversity, substance use, and enhancing healthy eating should also reduce rates of depression.