Depression as an Evolutionary Strategy for Defense Against Infection

Brain, Behavior, and Immunity 31 (2013) 9–22Contents lists available at SciVerse ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi Review Depression as an evolutionary strategy for defense against infection Sherry Anders a, Midori Tanaka b, Dennis K. Kinney c,d,⇑ a Clinical Psychologist in Independent Practice, Boxborough, MA, USA Obara Hospital, Sapporo, Hokkaido, Japan c McLean Hospital, Belmont, MA, USA d Department of Psychiatry, Harvard Medical School, Boston, MA, USA b a r t i c l e i n f o Article history: Available online 20 December 2012 Keywords: Depression Evolution Mood Inflammation Infection Infection-defense Immune Hypothesis Genetic Anti-depressants a b s t r a c t Recent discoveries relating depression to inflammation and immune function may help to solve an important evolutionary puzzle: If depression carries with it so many negative consequences, including notable costs to survival and reproduction, then why is it common and heritable? What countervailing force or compensatory advantage has allowed susceptibility genes for depression to persist in the population at such high rates? A priori, compensatory advantages in combating infection are a promising candidate, given that infection has been the major cause of mortality throughout human history. Emerging evidence on deeply rooted bidirectional pathways of communication between the nervous and immune systems further supports this notion. Here we present an updated review of the ‘‘infection-defense hypothesis’’ of depression, which proposes that moods—with their ability to orchestrate a wide array of physical and behavioral responses—have played an adaptive role throughout human history by helping individuals fight existing infections, as well as helping both individuals and their kin avoid new ones. We discuss new evidence that supports several key predictions derived from the hypothesis, and compare it with other major evolutionary theories of depression. Specifically, we discuss how the infection-defense hypothesis helps to explain emerging data on psychoimmunological features of depression, as well as depression’s associations with a diverse array of conditions and illnesses—including nutritional deficiencies, seasonal changes, hormonal fluctuations, and chronic diseases—that previous evolutionary theories of depression have not accounted for. Finally, we note the potential implications of the hypothesis for the treatment and prevention of depression. Ó 2012 Elsevier Inc. All rights reserved. 1. Introduction: rationale for an ‘‘infection-defense’’ hypothesis of depression Infection has been the leading cause of mortality throughout human history (Cairns, 1997; Finch, 2010). It has been estimated that prior to the industrial period, the average life expectancy was 25, and it was not uncommon for half of the siblings in a family to die before reaching adulthood (Cairns, 1997; Casanova and Abel, 2005). Particularly virulent pathogens could wipe out an entire family or village, such as the English ‘‘sweating sickness’’ known to have wiped out one-half to two-thirds of the population in many English towns during the late 1400s and early 1500s (Thwaites et al., 1997). With such stark capabilities, infection has been a critical and potent driving force in natural selection (Dobson and Carper, 1996). Specific alleles have evolved in response to common pathogens in an environment; however, pathogens are ubiquitous and wide-ranging, with new forms continually ⇑ Corresponding author. Address: 18 Locust Avenue, Lexington, MA 02421, USA Tel.: +1 781 862 1644, mobile: +1 617 271 5156; fax: +1 781 862 6559. E-mail address: [email protected] (D.K. Kinney). 0889-1591/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bbi.2012.12.002 evolving, leaving individuals intrinsically vulnerable (Casanova and Abel, 2005; Dobson and Carper, 1996). The ideal system of defense against this inherent vulnerability to infection requires a generalized response that is proactive in reducing infection risk during times of increased vulnerability, as well as both flexible and adaptive enough to provide resistance to a wide range of pathogens. Here, and in several recent papers (Kinney and Tanaka, 2009; Tanaka and Kinney, 2011a,b; Tanaka et al., 2012), we propose that moods—with their ability to orchestrate a wide array of physical and behavioral responses—have evolved as part of a complex system of immune defense that helps counteract our inherent vulnerability to the diversity of environmental pathogens. The ‘‘infectiondefense hypothesis’’ offers a novel evolutionary framework for understanding how many of the social and behavioral features of depression may help individuals fight existing infections, as well as help both individuals and their family members avoid new ones. In contrast to many previous evolutionary theories of depression, it takes into account and helps to integrate a large and growing body of evidence linking depression to inflammation and immune function, and helps to explain depression’s association with a vast array Schiepers et al. the role of immune-activated inflammatory cytokines has been identified as a key area of focus in understanding the neurobiological pathways that trigger depressive states. 2000. Behavior. The insufficiency of the monoamine hypothesis to explain critical aspects of mood regulation and the desire for more favorable treatment outcomes have resulted in an expanded search for the neurobiological underpinnings of depression. This is followed by a discussion of the infection-defense hypothesis (Kinney and Tanaka. These new lines of research— which show wide ranging links between depressive symptomatology and immune function—not only have the potential to lead to novel treatment strategies for the prevention and treatment of depression.. 2001). Raison et al. 1996. tumor necrosis factor-a (TNF-a). with estimates based on twin. 2005). including decreased fertility and increased mortality rates. 1990. 2012)... as depression is a risk-factor for many disease-related causes of death as well as for suicide (Mykletun et al.. 2006. known as the monoamine hypothesis. 2003) and the 5-HTTLPR short allele of the serotonin transporter gene (Eley et al. Depression thus poses a baffling evolutionary puzzle. seasonal changes. For more than half a century. From a global perspective. and behavior When infection or injury occurs. and by altering monoamine neurotransmitters in multiple regions of the brain (Dantzer et al. cognitive. but may also provide important clues as to the reasons for depression’s prevalence and persistence throughout human history. Klerman.. including sickness behavior. Increased mortality rates are also associated with depression. In addition. 2010. and is associated with increased rates of unemployment and divorce (Weissman et al. Raison et al. cognition. however. 1989).. adoption... Depression negatively impacts productivity. in which we propose that depressive features provide advantages in combating infectious diseases—advantages that offset many known disadvantages of depression.. Wender et al. We begin the paper with an overview of the epidemiology and neurobiology of depression.g.. despite its high costs for survival and reproduction. Schildkraut and Kety. weakness. and economic burdens as a result (Broadhead et al. 2006). prompting formulation of the ‘macrophage theory of depression’ (Smith. and genetic molecular studies consistently falling at about 40% (Kendler et al.. 3. We then describe several testable predictions of the ‘‘infection-defense hypothesis’’ and discuss empirical evidence that bears on each prediction. 2011a). and children of depressed mothers show poorer average outcomes on a wide range of developmental indices (Cummings and Davies. Anders et al. In particular. The estimated lifetime risk of a major depressive episode has risen to 23% in the United States (Kessler et al. 1999. 1989. 2009). 2000). Increased levels of proinflammatory cytokines—such as interleukin-1b (IL-1b). Cytokine-induced changes in somatic experience. 2007. This idea. Kendler et al.. 2006). the heritability of depression is well-established. 2007). 1996). proinflammatory cytokines produced by macrophages during the acute phase of an immune response act as neuromodulators that mediate the behavioral and neurobiological features of depression. depression will be the 2nd leading cause of disease burden worldwide (Murray and Lopez.1.. the initial promise of the monoamine hypothesis has been tempered by the fact that attempts to find direct links between monoaminergic transmission and mood have yielded equivocal results (Delgado.. the World Health Organization (WHO) has made the projection that. Compton et al. including suicide (Tanaka and Kinney. there has been a shift toward understanding the role of inflammation in depression. 2004.. 3. Sickness behavior—characterized by somatic. interleukin-6 (IL-6). Depression: an evolutionary puzzle While depression can occur at any point during the lifespan. efforts to understand the neurobiological underpinnings of depression have been dominated by the view that depression is caused by a deficiency in synaptic concentrations of monoaminergic neurotransmitters including serotonin and norepinephrine (Hirschfeld.. 2005). Eaton et al. The infection-defense hypothesis may also help to resolve a baffling evolutionary puzzle—why major psychological depression is so prevalent and heritable. a recent review of risk alleles for depression has revealed that in a striking majority of cases the depression alleles were associated with known effects on immune function (Raison and Miller. and its successive formulation as the ‘cytokine hypothesis of depression’ (Maes et al.. and there is evidence to suggest that the incidence of major depressive disorder may actually be increasing (e. Williams et al. 2011. such as fever.. We also briefly review other hypotheses and evidence that have related changes in immune function to depression. Schleifer et al. 2010). 2007). mal- . and chronic diseases. mood. Loftis et al. 2004. with estimates that between 30% and 50% of individuals treated with antidepressant medication do not show adequate response (Schatzberg. its most frequent onset occurs during the peak years of work and reproduction—and both depressed individuals and their family members often endure serious physical. has stimulated a wealth of research and has been the major driving force behind antidepressant drug development. and interferon-c (IFN-c)—have been repeatedly observed in depressed individuals. hormonal fluctuations. with adverse consequences noted even in cases where there has only been prenatal exposure to maternal depression (Davis et al.. such the CYP2C9⁄3 allelle (LLerená et al. Maes. the efficacy of antidepressant drugs based on the fundamental premise of the monoamine hypothesis has been limited. Genetic association and linkage studies have begun to discover specific alleles that increase risk for depression (see review by Goldberg. including recent updates linking depression to immune factors. According to the cytokine hypothesis. Sullivan et al. Heninger et al.. Immune alterations. as well as psychosocial functioning.... 2007). Zorilla et al. social.. Moreover. Irwin and Miller.10 S. In addition. 1967). Early studies investigating immune alterations during depression focused almost exclusively on markers of suppressed cellular immunity—such as decreased lymphocyte proliferation and natural killer (NK) cell activity (Reiche et al. Depression is associated with lower rates of fertility (Tondo et al. 2000. 1997.. 2000. and the macrophage and cytokine theories of depression Numerous associations between depression and immune function have been observed in recent years.. More recently. / Brain. 1986). despite the serious consequences of depression for individuals and their family members. proinflammatory cytokines are responsible for orchestrating the early immune response. 1995. Shyn and Hamilton. depression remains both common and heritable. 2006). 2001. by the year 2020. 1996). 1996). Research on the neuroimmune system and its role in the etiology of depression has emerged as an especially promising area for study. with a particular focus on the role of proinflammatory cytokines (Zorilla et al. Yates et al.. 1994). 1995. Over time. 2005). by way of direct and indirect effects on hypothalamic–pituitary–adrenal (HPA) axis. McGuffin et al. We conclude by comparing the hypothesis with other evolutionary theories of depression and by discussing some potential implications of the hypothesis for better treatment and prevention of depression. 2010. however.. and behavioral changes. 2008. and Immunity 31 (2013) 9–22 of conditions and illnesses such as nutritional deficiencies. 2. 1991).. withdrawal. like sickness behavior.. Serotonin levels are reduced due to the Table 1 A comparison of sickness behavior and depression based on the ‘‘infection-defense hypothesis’’. 2010. Segerstrom.. muscle and joint aches. 2010. thereby conserving energy. sleep disturbance). 1995). nearly all symptoms appear to help fight or avoid infection in some way. One of the most studied pathways by which cytokines may influence neurotransmitter metabolism.. but not necessarily. 2006).g.2.. help avoid new immune-compromising stressors. Wichers et al. A number of recent studies have also demonstrated links between inflammatory activation and brain changes that underlie depression (e.. Rausch et al. a major difference between sickness behavior and depression is that the costly antibiotic strategy of fever is notably subverted during depression (Maier and Watkins. including fever. Nevertheless. may not just be a spurious byproduct of cytokine-induced inflammation. although the two conditions are not equivalent (see Table 1). immune compromise Mode of Action Reactive Proactive and/or complementary.. and help individuals and their kin avoid new infections . 2004). 2003. decreased speech. norepinephrine. Capuron et al. 2008. Dantzer (2001.3-dioxygenase (IDO) (Capuron et al. however.. involves inflammation Adaptive Function Acute mobilization of resources to combat infection and promote healing Help combat existing infections. For example. guilt. 2006). 1988. 2005). Anders et al. injury Immune vulnerability. slowed speech. Duration Acute. melancholia may involve hypervigilance with agitation and insomnia that is less common in atypical. low motivation. Depressive symptoms are diverse and vary across patients and subtypes (e. 2011. 2010). Individuals who are most likely to develop depression during the course of cytokine therapy have been found to show increased baseline levels of proinflammatory cytokines prior to treatment (Wichers et al.. to exert both direct and indirect effects on monoamine neurotransmitter availability and metabolism (Dunn and Wang.. sleep disturbance. Behavior. 2006.. 2002. listlessness. and more severe levels of sickness-type behavior following initial administration of treatment (Robaeys et al. Kluger. Notably. or help combat existing infections Symptoms Circumscribed. a few days following cytokine administration.. and dopamine in areas of the brain that are associated with mood regulation (Rivier et al.. First.. symptoms of depression such as anhedonia. and even suicidal ideation (Capuron et al.. or seasonal subtypes). hopelessness. 2009.e. Pace et al. 3.. appetite disturbance. cytokine-induced symptoms of depression are attenuated by pretreatment with antidepressant therapy (Capuron et al. Loftis et al. 2009). fatigue. many patients experience sickness behavior. Proinflammatory cytokines have been noted. including sadness. A portion of individuals who experience sickness behavior go on to develop major depressive disorder. Second. Eisenberger et al. / Brain. postpartum. the therapeutic administration of cytokines such as interferon-a (IFN-a) and interleukin-2 (IL-2)—used to treat patients with cancer and a number of infectious diseases—has been found to induce a two-phase response.. decreased sex drive. IL-6. and somatic changes such as increased pain sensitivity. Maes et al. guilt. and mild hyperthermia.. 1998). Kinney and Tanaka. 1979). and these have been covered extensively in a number of recent reviews (e. and psychomotor retardation (i. 2006). 2009) has extended this notion to suggest that sickness behavior is an expression of a biologicallymediated motivational state triggered by the innate immune system that resets an organism’s priorities to adaptively cope with the threat of bodily insult. low self.. and there is suggestive evidence that milder temperature elevations. 2003).. 1989.. suicidal ideation. impaired concentration.. 3.S. including depressed mood. 2006.. 1986. Zhu et al.. Brydon et al. may act preemptively to avoid infection during times of increased immune vulnerability. Sickness behavior Depression Eliciting Conditions Infection. Neuromodulatory mechanisms of cytokines Multiple pathways have been identified by which cytokines exert neuromodulatory effects.. There is evidence that secondary development of depression following sickness behavior occurs in individuals who have an exaggerated vulnerability to infection (Dantzer. For example. IDO is activated by proinflammatory cytokines released during the acute-phase immune response.. up to 50% of those treated go on to develop symptoms of major depression. Kluger and Rothenburg. 2003). Dantzer et al. involves degradation of tryptophan by activation of the enzyme. malaise. 1988)—represents an organized strategy for fighting infection by conserving metabolic resources and helping an individual avoid further stressors (Hart. 2007). and body movements) all tend to reduce activity and encourage rest. Some studies have found that depression is associated with mild elevations in body temperature (e. for example. however. Several authors have suggested that depressive symptoms. feelings of worthlessness. including IFN-a. marked by neurovegetative and somatic symptoms (fatigue. as well as to increase activation of the hypothalamic–pituitary–adrenal (HPA) axis (Holsboer.g. sustained activation is biologically costly and harmful to host Sustainable for indefinite periods of time Inflammatory Response Sickness behavior always involves inflammation Depression commonly. impaired concentration. Capuron and Miller. Harrison et al. 2002).3. 2007. particularly when combined with reduced bodily iron stores. similar to sickness behavior. trauma.esteem. 2008. and impaired concentration (Hart. but may constitute an adaptive longer-term strategy for fighting infection (Raison et al.. Wichers et al. fatigue. loss of appetite Variable. 1999.. 2009. psychomotor slowing. 1997. and TNF.g. hypersomnia. A number of studies suggest that cytokines may decrease the amount of serotonin available for neurotransmission by up-regulating the expression and activity of the serotonin transporter (SERT) (Katafuchi et al. may be inhibitive to pathogen growth (Ismael and Bedell.. Yirmiya et al. 2000). hyperalgesia. 2000. 2009). Cytokines administered to laboratory animals and humans have been shown to alter the metabolism of the neurotransmitters serotonin. and Immunity 31 (2013) 9–22 aise. 1991. The costs of shifting resources and priorities during this state are purportedly offset by the critical advantages offered for fighting infection.. Miller et al. aches. Dantzer et al. 2009. Avery 11 et al. thinking. Sickness behavior and depression compared There are many parallels between sickness behavior and depression. 2008). Capuron and Miller. loss of appetite. Shuto et al. loss of interest and pleasure.g.. Depression also differs from sickness behavior in that its symptoms are more variable and include behavioral and cognitive features that discourage social contact and activity. aches. fatigue. indoleamine 2. genetic and seasonal variables. Cytokines increase glucocorticoid receptor resistance by way of several signaling pathways. Further evidence on the neuromeodulatory effects of cytokines comes from studies using functional magnetic resonance imaging (fMRI) techniques. 3. There are numerous examples of preventive immune strategies including. or indirectly. exposure to environmental toxins. create a dysregulation of the CRH feedback system and result in a feed-forward cascade that decreases the inhibitory effect of glucocorticoids on CRH and stimulates increased cytokine production. including. The immune system is an amazingly sophisticated system involving multiple. layered. Examples whereby costly adaptations have evolved because they offer compensatory advantages in defending against infection are numerous and widespread. 2008). By inhibiting social contact. nutritional status. What we are hypothesizing here is that natural selection may have also sculpted coordinated pathways between the nervous and immune systems so as to evolve behavioral response mechanisms that help prevent and combat infections. (2010) found that individuals receiving IFN-a for treatment of Hepatitis C were found to have higher cerebrospinal fluid (CSF) levels of kynurenine and its metabolites QUIN and KA. which can in turn be affected by a wide range of factors. Behavior. 1991. from an evolutionary perspective. In another study investigating the neural correlates of psychomotor slowing. Pace et al. second only in complexity to the nervous system. deeply rooted mechanisms have evolved. sleep disturbance. the infectiondefense hypothesis proposes that immune vulnerability to infection elicits depressed mood. Depressive signs and symptoms offer individuals advantages for fighting existing infections by helping to conserve energy and avoid environmental stressors and insults that could provide further immune-compromising challenge. behavioral responses. and strategic manner—an array of behavioral and immunological responses to infections and immune vulnerability. which in turn stimulates behaviors that help protect vulnerable individuals and their kin against infectious diseases. Although at first glance it may seem counter-intuitive. 4. The infection-defense hypothesis of depression (Kinney and Tanaka.. have noted the potential for such mechanisms: ‘‘It is quite logical to expect animals and people to also have evolved nonimmunologic disease-fighting strategies including behavioral patterns... 2009) offers an integrative view of these findings. The same research group has also reported findings that depressed mood and increased circulating levels of IL-6 following immune stimulation correspond to changes in areas of the brain highly involved in emotional processing. 2000. which helps to prevent contact with high-pathogen sources such as human waste and decaying flesh. Classic examples in humans in- Table 2 Key postulates of the infection-defense hypothesis of depression. IDO activity diverts tryptophan metabolism from the production of serotonin to the synthesis of its primary metabolite kynurenine. These changes.. despite depression’s significant costs to reproduction and survival. and reduced activity in the ventral striatum (VS)—the neural correlate of anhedonia—in response to reward cues. which in turn stimulates behaviors that help protect vulnerable individuals and their kin against infectious diseases (see Table 2). As Hart notes. that might serve as a first line of defense before the nonspecific and specific immunologic systems are activated and that would complement or potentiate immunological processes’’ (Hart. More specifically. and by stimulating changes in the expression of glucocorticoid receptor isoforms (Pace et al. as well. 1988 (p. 2008). offer a valuable potential advantage for combating infection—which is to avoid becoming infected in the first place. A number of studies have shown that inflammatory activation can stimulate changes in key areas of the brain that underlie depression. Specifically. it is precisely the high costs associated with depression. Cytokines may contribute to depression either directly. 2009). e. inflammation. resulting in the production of several neurotoxic compounds that may further mediate a depressive response (Dantzer et al. there must be some critical countervailing force or compensatory advantage that has allowed susceptibility genes for depression to remain in the population at high rates. (2010) found that research participants showed increased symptoms of depression. Scott and Dinan. and complementary strategies and mechanisms for helping individuals combat infections. 2002). 1. The ‘‘infection-defense hypothesis’’ of depression Advances in understanding the ways in which immune function. given such negative consequences. for example. and depression are related potentially provide clues as to why genes that increase vulnerability to depression have persisted at relatively high levels in the gene pool. they found increased subgenual anterior cingulate cortex (sACC) activity and reduced connectivity of sACC to mesolimbic regions of the brain including the amygdala. That natural selection has sculpted this incredibly complex system is testament to what a powerful role infection has played in natural selection. Immune vulnerability to infection elicits depressed mood. that argues for some adaptive advantage to depression. physical illness or injury. including Hart. For example. human aversion to noxious odors. depression also prevents individuals and their biological relatives from contracting new infections. in turn.. Cytokines activate the HPA-axis by inducing corticotropin-releasing hormone (CRH) and vasopressin (AVP)—key regulators of the HPA-axis that are found at increased levels in depressed individuals (see Owens and Nemeroff. also points in this direction.12 S. by which the nervous and immune systems can communicate and influence one another. Others. based on the idea that depression confers a critical compensatory advantage in immune protection that has offset notable disadvantages of depression for evolutionary fitness. Depression also has well-established links with hyperactivity of the HPA-axis (Pariante and Lightman.g. following experimental induction of an immune-inflammatory response. and that these increases were correlated with increased inflammatory biomarkers as well as depression. and stress. 4. These compounds. 2007). hormonal fluctuations. 2008). The potential importance of kynurenine metabolites in inflammatorymediated depression is underscored by the results of a recent study in which Raison et al. via activation of the HPA-axis. Compensatory advantages in combating infection are a promising candidate. combined with the fact that it is common and heritable. Eisenberger et al. which is further metabolized into several neuroactive compounds that include 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) or kynurenic acid (KA). Cytokines may contribute to HPA-axis hyperactivity indirectly. neural activity in the substantia nigra was found to correspond to increased levels of IL-6 and decreased reaction times following immune stimulation (Brydon et al. given that infection has had strong associations with morbidity and mortality throughout evolutionary history. 2007). generate free radicals that cause neuronal damage due to oxidative stress (Wichers and Maes. and Immunity 31 (2013) 9–22 breakdown of tryptophan by IDO. Anders et al. Increasing evidence that complex. That is.. 2. 2004). 123)). and superior temporal sulcus (Harrison et al. Holsboer. medial prefrontal cortex. in principle. in turn. 2000. / Brain. nucleus accumbens. including activation of the p38 MAPK. titrated. through cytokine-induced glucocorticoid-receptor resistance (Holsboer. through their effects on the glucocorticoid receptor. . Moods orchestrate—in a timely. hypersomnia. complex communities. When the female chooses the visually more attractive males. after all. often leaving the hive or burrow to die when they are ill—reducing the risk that they will expose others within their community to the infection. and/or (d) by helping individuals and their kin avoid contracting new infections (see Fig. yet it is very prevalent in tropical regions. will also be associated with increased rates of depression. Social withdrawal and decreased sexual drive. 5.. including sexually transmitted ones. Nery et al. and (4) act preemptively. as well as cues that discourage social contact from others—such as decreased speech. and/or (d) helping individuals and their kin to avoid transmitting or contracting new infections. for example. that depressed individuals exhibit statedependent increases in harm-avoidance behavior (e. low energy. conflicts. or that increase exposure to infection. Depressive signs and symptoms do this in four ways: (a) conserving energy. (b) directly enhancing immune function through antimicrobial action or by stimulating an increase in NK cell activity. The importance of reducing the spread of . 2. however.g. What we propose is even broader. A key aspect that distinguishes the infection-defense hypothesis from many other evolutionary theories of depression is that it proposes that depressive signs and symptoms not only offer individuals advantages for fighting existing infections. or injuries that can exacerbate existing immune system compromise. Moods help to regulate social behavior. de Winter et al. 2009). for example. These species are like humans in that they are social and live together in large. and changes in body language and facial expression (blunted affect)— can reduce the risk for contracting or transmitting infections. Most signs and symptoms of depression will aid the immune system’s ability to fight infections. Moods provide an implicit mechanism for cost-benefit analysis of an individual’s optimal responses to environmental challenges and the organisms’ immune status. 2007). depressive symptoms—such as increased bodily aches and fatigue. 13 (c) reducing the risk of further environmental stresses that impair immune function. (3) respond to immune vulnerability in a way that is both timely and titrated. Social withdrawal. Evidence relevant to the respective predictions is discussed in the following six sections. 2009). So why do it? Field studies indicate that it is adaptive because showy feathers and skillful dance signal to the females that the male carries fewer parasites. but also for preventing individuals and their biological relatives from contracting new infections. Depressed individuals will tend to have elevated rates of infection and/or immune alteration. (b) directly enhancing immune function through antimicrobial action or by stimulating an increase in NK cell activity. Moreover. (2) create responses that are generalizable to a variety of environmental challenges—a variety that reflects the inherent mutability and variability of environmental pathogens. (c) reducing the risk of further immune-compromising challenges. and psychomotor retardation—also reduce physical activity and encourage rest. thereby conserving metabolic resources for use by the immune system. irritability. 2000)—also discourage exploration and risk-taking. Many types of infectious diseases will be associated with depressive symptoms. Akin to the symptoms of sickness behavior present during an acute immune response to infection.. 2005). 2007. the degree of harm-avoidance behavior endorsed by depressed individuals increases along with increases in depression severity and the number of depressive episodes (Nery et al. Sickle cell anemia. and increases the likelihood that the male (and her offspring) will have better genetic resistance to infections in that ecological niche (see Kempenaers. such as thallasemia. she reduces her own exposure (and that of her offspring) to infection. and Immunity 31 (2013) 9–22 clude sickle cell anemia and other hereditary hemoglobinopathies. and have been known to display altruistic self-sacrifice. These predictions include the following: 1. irritability. 3. At first glance—from an evolutionary perspective—this is a rather puzzling phenomenon. but also reduce the risk of transmitting infection to relatives. the changes in social interest and demeanor associated with depression not only reduce an individual’s risk for contracting new infections by discouraging close contact with others. There are bidirectional processes that communicate between the nervous and immune systems and provide mechanisms for infections. and increases visibility to predators. and physiological conditions that increase immune vulnerability. is a hereditary disease that is typically fatal. Evidence for prediction # 1: most signs and symptoms of depression appear to aid the immune system’s ability to fight infections As the infection-defense hypothesis predicts. / Brain. environmental. 5. Some testable predictions of the infection-defense hypothesis A number of testable predictions follow from the infection-defense hypothesis. and mood to influence one another. This may allow depression to serve as a complementary line of defense when the early immune response to infection cannot be sustained during extended periods of infection or immune vulnerability. Anders et al. 1).. Behavioral strategies that defend kin against risk of infection can also be noted in species such as honey bees and African naked mole rats (see Preti. it takes significant energy and metabolic resources for the birds to produce those ostentatious feathers and dances. Behavior. 6. as they have the ability to (1) orchestrate a wide range of behaviors. In addition to these somatic and behavioral changes that occur during depression. An example from nonhuman species involves the evolution of eye-catching plumage and courtship dances that peacocks and the males of many other avian species use to woo females. 2007). based on both endogenous and environmental signals of increased infection risk. Medical. moods potentially provide an attractive system for behavioral defense against infection. 6. Considerable evidence exists to support each of these predictions.. while depressive states are more sustainable than sickness behavior over longer periods of time by reducing the high cost of fever. allowing the gene to persist despite its severe costs (Kwiatkowski. may greatly reduce the spread of infections by discouraging mobility and/or social contact with others. helping to regulate the timing and intensity of infection-defense responses. for example. anhedonia and cognitive features of depression—such as decreased self-esteem and feelings of hopelessness (American Psychiatric Association. there is evidence that most features of depression appear to aid defense against infections. thereby reducing exposure to new pathogens or to accidents. and blunted affect. From an evolutionary perspective. Thus. People who inherit only one copy of the sickle-cell gene have increased resistance to malaria. immune processes. Depression’s overlapping features with sickness behavior appear to help conserve energy and avoid further immune challenges. by performing one or more of the following functions: (a) conserving metabolic resources for use by the immune system in fighting infection.S. 4. A number of studies have found. 2003.14 S. may also have the effect of minimizing exposure to out-group members. have a number of known anorectic effects. / Brain.. However. some forms of depression. and insomnia. which plays a key regulatory role in balancing food intake and energy expenditure (Andréasson et al. sleep deprivation. for example.. Dantzer. a major source of infection throughout history and the present (Mead et al. and increased appetite/carbohydrate cravings. 1Depressive symptoms vary by subtype. chronic infection and disease. (c) reducing risk of further immune challenge. Reduced mobility and reduced sociability associated with depression. (b) directly aiding immune defenses through antimicrobial action and/or by increasing NK cell activity. 2004). Reduced appetite can reduce the risk of food–borne parasites. or restricting patterns of eating to avoid food-borne illness. including seasonal affective disorder (SAD). while at the same time being less likely to cause illness due to spoiling than many other foods. In spite of high metabolic costs. agitation. such as sugar and baked bread. 2000). 1997). Behavior. such as avoiding danger or conflict to reduce the risk of physical injury.g. It has also been noted that high intake of carbohydrates can promote defense against infection by decreasing the relative intake of lipids. 1999). Some individuals with depression develop paradoxical symptoms that include notable anxiety. such as meat. are associated with increased carbohydrate cravings. Appetite changes are extremely common in depression. 2009). According to the infection-defense hypothesis. Thwaites et al. while other forms of depression – such as melancholia – include symptoms of restless agitation. exposure to toxins. depression among human mothers. where the threat . or fruits and vegetables. Depressed individuals can vary in whether they tend to increase or decrease overall intake of food (American Psychiatric Association. and/or (d) by reducing the spread of infection through decreased social contact.. 2004). In addition. Contact with individuals from different groups or environments who are immunologically dissimilar increases the risk of exposure to pathogens to which an individual has not developed specific immunity in their home environment. seasonal affective disorder (SAD) and other atypical forms of depression often include symptoms of psychomotor slowing. as noted by Raison and Miller (2012). A neuro-immune feedback system regulates the timing and intensity of behaviors that aid defense against infection.. accounting for seemingly paradoxical symptoms involving energy and appetite. By contrast. constituting a state of hypervigilance. as lipid consumption has been associated with worse outcomes for infectious illness (Heyland et al. increased intake of carbohydrates influences immune function by triggering changes in proinflammatory cytokines and an increase in NK cell activity (see Braun and Von Duvillard. offer high metabolic and caloric resources. which in turn reduce immune vulnerability and risk of infection by (a) conserving or enhancing metabolic resources for fighting infection. anorexia. and Immunity 31 (2013) 9–22 Fig. The nascent immune system of infants and young children render them especially vulnerable to infections. as well as sickness behavior among murine animal models. Carbohydrates and carbohydrate-based foods. is associated with disengagement—and sometimes even rejection—of offspring (Burke. hypersomnia.. the specific forms that these appetite changes take in depression may constitute alternative strategies that help defend against infection. depression and related behaviors that aid against infection are activated by immune status. hormonal fluctuations. Proinflammatory cytokines. Anders et al. Consistent with the notion of a heightened need to protect the young. heightened vigilance is likely to have been an extremely adaptive response to stress throughout human evolution. including increased stimulation of the peptide leptin. 1998). 1. infection to others is highlighted by many examples throughout human history whereby infectious diseases were known to wipe out entire families or villages (e. 2007. fish. as well as by a number of other known immune-compromising factors that include stress. and insomnia. Wong and Pinkney. and nutritional deficiencies. For example. winter season. Immune vulnerability is influenced by acute risk of infection. Cohen et al.. Those who had been diagnosed with the more severe form of WNV. high viral loads are associated with higher depression scores on the Hamilton Rating Scale for Depression (Cohen et al.. 2009. 2002a). 2003. Stress. Murray et al.. 2002b. 2000). 2000). 2003). 1996). Depressive symptoms are also significantly associated with recurrence of herpes simplex infection (Zorilla et al. For example. Afsar et al. Another major risk factor for depression is chronic insomnia (Lustberg and Reynolds. Evidence for prediction # 2: many types of infection are associated with depression Increased rates of depressive symptoms have been observed following an individual’s contracting a number of acute or subacute infections (Fazekas et al.. 2007). Among HIV patients. (2007) found that over 31% of WNV patients in their study experienced the onset of a depressive episode within one year of their becoming infected.. Evidence for an increased risk of depression among those who suffer from chronic infections comes from a variety of studies involving both humans and laboratory animals.... Depressed individuals most often show evidence for increased levels of the proinflammatory cytokines IL-1b. 2001). Zorilla et al. 2001). and populations that experience higher levels of social stress tend to have higher rates of mortality and morbidity from infectious disease (Weiss and McMichael. autoimmune diseases. 2004). increased depressive symptoms have been found in patients with herpes simplex encephalitis (Fazekas et al. 2006. Kiecolt-Glaser et al. 2008. hormonal fluctuations. and glucocorticoids (Loftis et al. although the results are less consistent. for example.. 8. depressive symptoms are associated with higher viral load and lower NK cell activity (see review by Kopinsky et al. Depression-like behavior has been observed. For example. 1996) and reduced cellular immunity to varicella-zoster (Irwin. for example. 2010. 2000). Chronic sleep deprivation is associated with increased immune vulnerability (Irwin. Evidence for prediction # 4: many conditions associated with immune vulnerability are also associated with depression The list of conditions that show associations both with increased vulnerability to infection and with elevated risk for depression is long and varied. Evidence for prediction # 3: elevated rates of infection and/or immune alteration are found in depressed patients Just as elevated rates of infection would be expected among individuals with fever. neuroinvasive disease. 2007... Irwin and Miller. IL-6. Among certain sub-groups of older adults. nitric oxide. Two widely-studied factors linked both to immune vulnerability and to depression include stress and sleep deprivation. Increased levels of proinflammatory cytokines and chronic inflammatory response have been found repeatedly in depressed individuals (Dowlati et al. 2002). 2005. Vaccines containing live viruses can also cause depressive symptoms. contributing to the hypersecretion of cortisol (Turnbull and Rivier. accompanied by a rise in serum levels of IL-6 (Glaser et al. 1998).. 2002.. In another study.... Among HIV-infected patients. C-reactive protein (CRP). is also associated with increased numbers of circulating proinflammatory cytokines (Bierhaus et al. 2004). 2010. 2005) and elevate core body temperature. reduce risk of exposure to new infections or immune-compromising injuries and stressors. it has been found that stressed caretakers are more vulnerable to infectious diseases (Kiecolt-Glaser et al. 1994). in a prospective double-blind study (Yirmiya et al. 2006) and West Nile virus (WNV) (Murray et al. 2001). and immunization with live virus vaccines (Afsar et al.. thereby discouraging them from adventurous activity outside the home.. Accordingly. Poor sleep quality and insomnia can precipitate . Cortisol can suppress cellular immune response that is critical in defending the body against viral infections (Maes et al. Furthermore. such as human immunodeficiency virus (HIV). 2007. 2002a). Mundt et al.. Accordingly. a robust association has been found between depressive symptoms and reduced NK cell activity (Zorilla et al. 2001.S. there is evidence that chronic stress significantly increases vulnerability to infection (e.. Zorilla et al. cardiovascular disease. 1989).. given our proposal 15 that depression is elicited as an immune defense during conditions of infection or immune-compromise. although speculative. Sillaber et al. 2000). Kendler et al.. Yirmiya et al. 2003.. 1999. 2009). which has a clear and well-established role in the etiology of depression (Brown et al. O’Connor et al. Irwin. 2004). have also been found to have an increased risk for depression (Yates and Gleason. for a review). Lipkin and Hornig. toxin exposure. which has been identified as a critical pathway in central nervous system (CNS) dysregulation.. moderate physical activity can increase NK cell activity (Nieman et al. Depression has also been associated with decreased lymphocyte proliferation. as well as greater vulnerability to infection (Cohen. influenza vaccination has also been linked to increased depressive symptoms. depressed individuals show marked evidence of immune suppression and excessive inflammation (Dowlati et al. For example. and Immunity 31 (2013) 9–22 of predators and other physical dangers to self and family was high (Marks and Nesse. 1995). 2009.. 2010. 2009). An agitated state tends to occur in the context of patients’ increased anxiety about their personal safety and that of their family.. as well as following chronic infections (Cohen et al.. 2009). which may have additional immune effects (Mestre-Alfaro et al. Anders et al. Hypervigilance may contribute to harmavoidance behaviors that. Humans suffering from chronic infections. 2004. 1986. Hammen. 2002). haptoglobin.. 2009). nutritional deficiencies. Zorilla et al. in mice infected with Bacille Calmette Guerin (BCG). which can occur during agitated forms of depression. 9. For example.. / Brain. and INF-c (Maes et al. Lipkin and Hornig. 2012.. 2004).. 1998. 1994)... Irwin. 2002b). 2001. Murray et al. Other inflammatory biomarkers that have shown regular associations with depressive symptoms include changes in acute-phase-response protein. (2009) found increases in symptoms of depression related to antibody response following Hepatitis B vaccination in hemodialysis patients. 1995. Zorilla et al. 7. hepatitis C (HCV). 1995. and the severity of insomnia is negatively correlated with NK cell activity in both depressed and non-depressed groups (Zorilla et al. Maes et al... cancer. so that the increased exercise occurs in a way that reduces the risk of injury and contact with new infections that would otherwise tend to occur as a result of increased exercise. and genital herpes (HSV-2). Irwin and Miller.. 2007). Reiche et al. TNF-a. and appear to depend on moderating factors such as age (Schleifer et al. 1995). and includes seasonal factors. Behavior. as noted earlier. a bacterium related to the one that causes tuberculosis (O’Connor et al.g. restless pacing or hand-wringing.. Wolf et al.. 2002.. Horesh et al. showed an even greater risk for developing depression. may offer some benefits to immune function just as other forms of moderate physical activity do. Increased cytokines sensitize the HPA-axis. 2012). 2009. A number of studies indicate that depressed individuals show increased vulnerability to contracting infections. For example. vaccination with live attenuated rubella virus resulted in depressive symptoms that lasted up to 10 weeks. 1999. elevated rates of infection and/or immune alteration are expected in depressed patients. and chronic pain (see Tanaka et al..... Glaser et al. Cohen. such as upper respiratory tract infections (Cohen. Yates and Gleason. among participants in a mindfulness-based stress reduction program. Therefore.. hormonal fluctuations associated with the menstrual cycle and post-partum period (Groër and Morgan. cardiovascular disease (Cesari et al. 1992.. Dantzer et al. In a recent review... 2003. Pace et al..g. 2008. There is also evidence that the timing of mood response to antidepressant interventions parallels changes in immune function (Lieb.. In experiments with rats. Studies of meditation practice also show notable effects on stress and immune responses. Kronfol et al. the list of conditions that are associated both with immune vulnerability and with depression is staggering and diverse. It has been proposed that psychotropic medications derive their antimicrobial properties by acting as bacterial efflux pump inhibitors (EPIs) (Munoz-Bellido et al. 1995) have also found depression severity to correlate with circulating numbers of proinflammatory cytokines.. Udoji et al. (2010) found that NK cell activity was significantly enhanced only in patients who reported improved well-being following the intervention. 2010). 2000. A preponderance of cross-sectional research in these areas limits causal interpretations and highlights the need for more longitudinal investigations. They include seasonal factors such as reduced daylight hours and colder temperatures during the winter months (Lam et al. and proinflammatory cytokines (Motivala et al. An extension of this is that mood elevation can stimulate more adventurous or gregarious behavior when an individual is in a more robust immune state. 2003). Anders et al. 2008). 2007. For example. Kronfol et al. These effects include the ability to reverse resistance of bacteria to antibiotics (e. Murray et al.. Depressive behaviors are biologically costly. Behavior. Beseler and Stallones.. Robinson et al. 2008). therapeutic administration of ketamine. high viral loads were associated with higher depression scores on the Hamilton Rating Scale for Depression (Cohen et al. chronic restriction of sleep causes depression-like changes in both the sensitivity of neurotransmitter receptors and neuroendocrine reactivity to stress (Novati et al. 2010). or when an individual suffers from chronic infection or stress. 2007) and degradation of tryptophan by activation of the IDO (Capuron et al. 2008). 2006. Magnusson. Maes et al. as mentioned above. 2002). Rubinow et al. territory. For example.. 2000).16 S. 2006. 2008).. C-reactive protein (CRP). however. Evidence for prediction # 6: moods orchestrate the timing and intensity of infection-defense behaviors There is evidence that moods also provide a mechanism for regulating the timing and intensity of immune-related behaviors based on an implicit cost-benefit analysis of what is most adaptive for survival and reproduction. and antidepressant . autoimmune diseases (Gold and Irwin. while those who had been diagnosed with the more severe form of WNV.. demonstrated an even greater risk for depression. 1998). 2009. Hibbeln.. There is evidence that NK cell activity is significantly elevated after experimental exposure to pleasurable conditions (Berk et al... exposure to environmental toxins such as toxigenic mold and pesticides (Anyanwu et al. measured by telomerase activity.. 2008).. 2002... as well as with measures of HPA-axis hyperactivity.. In addition to stress and sleep deprivation. Nery et al. Sillaber et al. and chronic pain (Watkins and Maier. 2004. Kling et al.. including activation of the HPA-axis by proinflammatory cytokines (Holsboer. 2003..g. There is now well-established evidence to suggest that bidirectional communication between the immune system and nervous system also occurs (Maier and Watkins.. Bidirectional communication between the immune and nervous systems is suggested by the immune-enhancing effects of antidepressant interventions. 2003. Witek-Janusek et al. 2012. 2000).. 2008). (2007) found a heightened risk for depression among a group of individuals who had contracted WNV disease... Sickness behavior and depression (and perhaps various sub-types of depression) are elicited—and vary in timing and intensity—based on feedback from the immune system. 10. the benefits would outweigh the costs only when initial efforts to cope with an immune challenge are ineffective. and a number of medical or physiological conditions such as cancer (Miller et al... 2007. 2002).. 2009). / Brain. (2009) found that among individuals undergoing training for compassion meditation. 2011. 2010. Witek-Janusek et al. and meditation practice (Lavretsky et al. Evidence for prediction # 5: bidirectional links between the nervous and immune systems allow moods and immune vulnerability to influence each other Multiple pathways have been identified by which immune system activation may lead to depression.. In a study of HIV patients.. For example. 2003. That such a wide array of conditions has well-established links with both depression and immune alteration is consistent with the notion that depression evolved as a generalized immune response that can offer broad defense against a range of immune challenges. 2012). also enhance NK cell activity (Masuda et al. In another study (Lavretsky et al. 2010. Matsunaga et al. 2003. and that psychological interventions for the treatment of depression and emotional distress.. and especially in pre-modern times would likely interfere with efforts to acquire and compete for food. such as mindfulness training and cognitive behavior therapy (CBT). 2000). (1994. Hestad et al. including IL-1 and IL-6. McNamara et al. interfering with work and social functioning. neuroinvasive disease. such as electroconvulsive therapy (ECT) (Fischler et al. a variety of psychosocial interventions (Fang et al.. a number of experimental studies have reliably demonstrated that conditions associated with sources of immune vulnerability such as stress and sleep deprivation increase risk of depression-like behavior in animal models (e. Robinson et al. 2003). the amount of time spent in meditation practice was associated with decreased IL-6 concentrations and decreased levels of distress following exposure to a laboratory stressor. raising plasma cortisol. 2010. with a gradual and significant decline in TNF-a levels over the course of repeated sessions (Hestad et al. 2007). 2011b). In a recent paper. Several types of antidepressants and mood stabilizers are also noted to have antibiotic effects. Ardayfio and Kim. 2008. Novati et al. Evidence from a number of studies indicates that risk for depression and depression severity varies in relation to immunecompromise. nutritional factors such as deficiencies of Vitamin D or Omega-3 fatty acids (Borges et al. dementia caregivers who practiced daily yogic meditation experienced a reduction in depressive symptoms and reduced signs of stress-induced aging. Pace et al. 2008.. Pace et al. and mates. Lieb (2007) cites a number of in vivo and in vitro studies demonstrating that antidepressant drugs and lithium have significant antimicrobial and immune-potentiating effects. Kristiansen et al.. Lieb (2007) also notes that several antibiotics have been found to have mood-enhancing effects.. Tanaka and Kinney. Notably. 11.. and Immunity 31 (2013) 9–22 inflammatory processes.. 2009). 2009). 2006). 2001. 2008). augmented NK cell activity is found after a single session (Fischler et al. Ganji et al.. 2002.. Corsini et al. while ECT—known for its rapid amelioration of depressive symptoms— shows no evidence of changes in monoamine metabolism or neuroplasticity following a single ECT session.. Tanaka and Kinney (2011b) reviewed studies that provided information about the time course of mood response and NK cell activity following a number of mood-enhancing interventions such as exercise. 2005). Parker et al. Fang et al. 1992.. hypervigilance. by contrast. The infection-defense hypothesis. The two hypotheses differ. the fact that depression has persisted despite these costs only strengthens the case that it must have offered a powerful adaptive advantage for risk alleles to have remained so high in the population. while the long-term effects of chronic immuneactivation or inflammation only become more relevant as life expectancy gradually increases over time. Lieb (2007) described evidence that antidepressant drugs and lithium demonstrate concomitant increases in mood-response and immune-potentiating effects. Price et al. Throughout human history. Each theory hones in on selection pressures that have likely shaped affective responses throughout evolution. conservation/withdrawal behavior.’ offers a more general model of depressed mood. immune responses are likely to be biased toward surviving acute or relatively short-term immune challenges. however.S. 12. (2) in their ability to explain the full range of signs and symptoms of depression. / Brain. 2003). contribute to the etiology of depression. Traditional evolutionary theories of depression. . from a Darwinian perspective. an adaptive view of depression does not imply that depression can’t sometimes be harmful. For example. thus. can be theoretically de-coupled from immune activation. and can promote adaptive behavior in response to the types of losses or conflicts described above. 1994). provides important feedback to self and others about social and environmental sources of stress. and potential ‘‘third variables’’ that may be influencing immune response. according to ‘rank theory. An exception to this is Raison and Miller’s (2012) recent hypothesis of pathogen host defense (PATHOS-D). However. 2008) and cancer (Reiche et al. pervasive sense of sadness that often occurs in the context of clinical depression may help to promote withdrawal behaviors that conserve energy and reduce exposure to new sources of stress or infection. seasonal changes. ‘‘second-line’’ posture that offers protective advantages in response to defeat. mediated by a variety of neuroimmune processes. there is currently little in the way of systematic attempts to help explain depression from an evolutionary infection-defense point of view. suggesting that it provides affective feedback that discourages continued investment in adverse or unreachable goals (Thornhill and Thornhill. thus. including apparently paradoxical features such as hypervigilance vs. 13. The infection-defense hypothesis. the impact of infection on survival and reproduction has been staggering. we would expect depression to be elicited more often in the context of illness and disease. From our infection-defense perspective. More longitudinal data is needed to provide an accurate account of the progression and relative contributions of depression. following a similar time course. heightening attention to adversity. More traditional attempts to explain the persistence of depression from an evolutionary standpoint have focused on socially adaptive mechanisms. Potential challenges to the infection-defense hypothesis Depression’s associations with higher morbidity and mortality rates for a number of diseases appear to contradict the notion that depression provides an evolutionary advantage. however. but also presages worse outcomes for a number of illnesses. 2004). Notable parallels in the time course of mood improvement and immune response were observed across all modalities. inflammation. and confer risk in others? Just as fever. 1989). however. Evolutionary theorists have often drawn upon key features of depression—such as sadness and withdrawal—as part of a subversive. reduced bodily iron stores. In a separate review. Comparison of the infection-defense hypothesis with other evolutionary theories of depression Although the proliferation of recent evidence linking depression to inflammation and immune function has led some to speculate about the potentially adaptive role of depression in helping fight infections. and Immunity 31 (2013) 9–22 treatments. Drawing on evidence that many genes identified as risk alleles for depression are also associated with immune factors related to pathogen host defense—such as hyperthermia. as a way to maintain social ties critical for survival and reproduction (Allen and Badcock. (3) in their ability to explain depression’s association with a diverse array of conditions and illnesses such as nutritional deficiencies. and offers insight into the mechanisms by which many known risk factors for depression. in their explanations of how depression relates to immune activation. that our hypothesis only requires that the relative advantages of depression outweigh its costs. 2011). According to PATHOS-D. and life expectancy throughout most of human history was less than half of what it is today. Other theories describe ways in which behavioral changes and nonverbal cues associated with depression function as distress signals to elicit help during adversity (Hagen. on the other hand. For example.’ depression signals yielding behavior following an unsuccessful struggle for dominance in order to avoid unnecessary harm (Gilbert. genes that are involved in immune response and depression are one in the same. The ‘psychic pain hypothesis. there would be extremely high rates of morbidity and mortality associated with it. There may be other ways to understand depression’s persistence from an immune standpoint. 2006. on the whole remain limited (1) in their ability to offer predictions that can be submitted to rigorous testing. 1992). might depression simply be an epiphenomenon of a prolonged or severe inflammatory response? Or is it possible that depression is a maladaptive expression of genes that confer immune advantages to the host under some circumstances. Similarly. Moreover. and anorexia—PATHOS-D. Behavior. and depression is intrinsically tied to immune activation. for example. There is some evidence to suggest that depression not only follows.. helps to integrate a large and growing body of research that depression is intimately linked with immune function. which is consistent with evidence that depression is commonly—but not always—associated with an immune-inflammatory response (Raison and Miller. sadness. self-limiting features. ‘social risk theory’ describes depression as a signal of submissiveness in response to social failure. the 17 immune system co-opts this affective response so that the deep. For example. conservation/withdrawal states. and helps to explain many of depression’s puzzling. From the infection-defense point of view. suggesting that well-established mechanisms for communication between the immune system and the nervous system provide pathways for depression to be triggered and modulated by infections as well as other signals of vulnerability. a key asset in combatting infections. suggests that the advantages in pathogen host defense conferred by depression risk alleles offset depression’s notable costs to reproduction and survival. and both of these effects tend to dissipate within several hours after the conclusion of exercise. It is important to note. the view that depression is a fundamentally maladaptive state is again refuted by the notably high prevalence rates of depression risk alleles in the population. such as stress and sleep deprivation. and (4) in their failure to account for evidence that depression is linked to immuneinflammatory factors. while offering potentially useful explanations for understanding changes in affect and behavior under a circumscribed set of conditions. can be harmful or even lethal at high levels. like the infection-defense hypothesis. and chronic diseases. hormonal fluctuations. both mood and NKCA are rapidly enhanced in response to exercise. including HIV (Leserman. Anders et al. This inflammatory response is stimulated by increased production of proinflammatory cytokines.. For example. Chapman et al. as noted above. Gillespie et al. 2007). may be better explained from an ethological attachment framework (Bowlby. At any given point in time. for example. Early adverse experiences such as neglect and trauma are related to increased risk for depression and disease across the lifespan (Chapman et al. as the increasing rates may not be due to increased genetic risk per se. and adults with a history of childhood maltreatment have been found to respond to acute stress with increased IL-6 concentrations compared to controls (Carpenter et al. and in particular. 1982. This emergent model of depression helps to explain: (1) why depression is associated with immune alterations such as decreased NKCA... 2010). despite depression’s association with increased morbidity and mortality. carry important implications for understanding the causes.’’ that may contribute to inflammation-associated depression. and (3) reduce social contact to prevent the spread of infection to kin. the notion that moods may serve as a behavioral defense against infection. and have been implicated as key factors mediating the associations between early experience. 2006). the role of increased hygiene and availability of antimicrobial treatments in modern society have reduced mortality rates associated with infection. vulnerability to infection. Evidence from studies using both human and laboratory animals suggest that early life experiences can influence susceptibility to inflammation and depression. including classicallyconditioned stress responses to situational triggers. Walker. such as increased translocation of lipopolysaccharide (LPS) from gram-bacteria. signs and symptoms of depression such as anhedonia. For example. then the goal of reducing depressive symptoms to ease emotional distress should be balanced against the need to first identify and treat possible .. 2009). Future studies using longitudinal and epidemiological data will also be important in helping to establish the relative progression of immune-inflammatory factors and depression following exposure to infection or immune-compromising conditions. psychological interpretations of depression—including psychodynamic or schema-based interpretations—insofar as they help to identify and alleviate sources of psychological stress. Increased CRH concentrations and HPA-axis activity are found in both humans and laboratory animals who have experienced early life stress. 2011). and (3) why a wide range of environmental and physiological factors associated with increased vulnerability to infection are also associated with increased risk for depression. For example. immune vulnerability (Dantzer et al.. 2008.. and/or chronic activation of the innate immune system. grief-related depression following the loss of a loved one is more likely to elicit crying. / Brain. complement an infection-defense view of depression. and depression (Bradley et al. social withdrawal.. 2010). (2) why depression is associated with increased rates of infection and disease. have outlined factors related to the condition of increased gut permeability. Raison and Miller. 2008. that carriers of the 5-HTTLPR short allele demonstrate an elevated risk for depression that is further increased in relation to levels of environmental stress (Eley et al. 2009). and situational triggers (Keller and Nesse. which have wide-ranging effects on both neuroendocrine and neuronal systems. 2004. 2000). some depressed individuals experience hypervigilant states that include agitation and restlessness. 2010). 2007). Behavior. but also supports an integrative framework for understanding the etiology of depression from multiple levels of influence. but rather to the increased presence of immune-compromising factors such as environmental toxins.18 S. it remains to be seen whether some forms of depression are better explained from alternate bio-behavioral frameworks.. 2006). physiological vulnerabilities (Maes et al.. inflammation. as in the case of the 5-HTTLPR short allele of the serotonin transporter gene. 2011). 2009. while others experience low energy and psychomotor slowing (American Psychiatric Association. Kinney and Tanaka. 2005). Anders et al. 1990). While not all individuals who experience depression show evidence of increased inflammation (Raison and Miller. Summary and further clinical implications of the infectiondefense hypothesis Converging evidence suggests that depression is often an inflammatory/immune-mediated response to infection. the discovery of inflammatory-immune factors in the physiology of depression helps to explain an important psychiatric puzzle as to why genes associated with major depression have persisted. It is also of note that. The infection-defense view of depression not only helps to provide an evolutionary explanation for the prevalence and persistence of depression throughout human history. reduced energy and psychomotor retardation— and the genes that contribute to them—may be explained as adaptive responses to infection vulnerability that serve to: (1) conserve metabolic resources for fighting infection. In addition. using a double-blind placebocontrolled experimental design. As outlined in the infection-defense hypothesis. Given the complex interplay of multiple systems involved in a depressive response. Kendler et al. (2) reduce exposure to further infections or environmental stressors. 2012). if symptoms of depression are serving a protective function in the face of immune challenge.. immune response may also interact with other physiological vulnerabilities to increase risk for depression. key tenets derived from the infection-defense hypothesis can be submitted to rigorous testing. Unlike many other evolutionary theories of depression. grief reactions to separation and loss. 1990). A comprehensive view of depression A comprehensive view of depression takes into account its multi-faceted nature that manifests in a variety of clinical presentations.. including an inhibitory influence on serotonergic transmission. Mikulincer and Shaver. for example. While the infection-defense hypothesis posits a protective role for depression in humans’ environment of evolutionary adaptedness. 15. Clinical Implications Associations between immune function and depression. Numerous studies have shown. whereas depression that follows from stress or seasonal factors is more likely to involve pessimism and fatigue (Keller and Nesse. 2004. Maes and colleagues (Maes et al. rooted in survival strategies employed during the vulnerable state of infancy. and prevention of depression. Some of these implications pose a challenge to conventional wisdom. 2009. and suggests the possibility that depression’s relative advantages in infection-defense may be decreasing. Childhood maltreatment is also associated with increased inflammation (Danese et al.. 2008. Laboratory studies using rats have found that impaired maternal contact and milk quality can induce significant changes in stress response and inflammation in offspring (Walker. 2004.. from a clinical perspective. a stringent test of the hypothesis that interventions reducing infection and/or immune compromise will lead to a reduction in depressive symptoms could be made.1. Garnefski et al. The fact that rates of depression are increasing does not necessarily counter this. the specific features of depression that are evoked likely depend on the interaction of genetic factors (Raison and Miller.. Garnefski et al. For example. early experience (Bradley et al. for example. treatment. Gene-environment interactions have been found to exert influence on depression risk. and Immunity 31 (2013) 9–22 14. known as ‘‘leaky gut. 15. American Psychiatric Association. 2009).E. meditation practice. A. as well as pharmacological interventions.. such as correcting nutritional deficiencies or engaging in stress-reduction activities like meditation. Raznahan. 607–611. Biol. TNF-a inhibitors have shown promise in clinical trials for decreasing symptoms of depression. 2003. Ehiri. Antibody response following hepatitis B vaccination in dialysis patients: does depression and quality of life matter? Vaccine 27. For example.... such as more thorough and frequent handwashing. Elsurer. E. 2009). and pain perception (Roque et al. the potential role of underlying infections and immune disorders warrants greater attention. stress. Prog. and other pollutants. in particular. M. 2010). The notion that depressed individuals may have increased immune vulnerability.. Kamalipour. Some factors that influence immune vulnerability. S. and Immunity 31 (2013) 9–22 underlying immune factors.N. 2010). Increasing levels of environmental toxins that contribute to inflammation and depression may potentially help to explain recent increases in rates of depression (Compton et al. Another promising line of research in the search for improved pharmacologic treatments of depression involves anti-inflammatory cytokine antagonists. the use of the IL-1b receptor antagonist IL-1ra prevented the development of depression-like behavioral and neurochemical changes in response to chronic stress exposure (Koo and Duman. Another TNF inhibitor. 3. Jones. celecoxib. In summary. M. DC. Finally.A.. 5865–5869. Eder.. Conflict of interest All authors declare that there are no conflicts of interest. The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures. and to weigh the potential risks of anti-inflammatory/immunosuppressant agents against the need to alleviate depressive symptoms. celecoxib has been found to augment the antidepressant effects of fluoxetine (Akhondzadeh et al. 1128–1137. 2012). or other source of immune compromise leads to several further implications. B. In addition. such as stress and sleep disturbances. immune-enhancing.B... moderate exercise. D. Lekander. increased attention to hygiene in clinical settings such as waiting rooms. This need is underscored by the findings of Rabinowitz et al. 2006. Jafari. Diagnostic and statistical manual of mental disorders text revision (4th ed. 2009. 2000. M. Anyanwu. dietary deficiencies. Psychiatry 30.. 249–256. helplessness. Caglar.. 2003). 2007. Preliminary findings suggest that non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin.B. 2006). D. shared bedrooms on inpatient units. Brain Behav.. Environmental pathogens that trigger immune impairment and inflammation.. or anti-inflammatory properties also merit more study for their potential antidepressant effects. Raisi. Finally. minocycline. S. to help temper symptoms of depression. Eyileten. exposure to toxigenic mold is associated both with alterations in both NK cell activity and various neuropsychiatric symptoms. A. Patients with treatment-resistant depression who had high baseline levels of inflammatory biomarkers showed improvement following several infusions of the TNF antagonist Infliximab over a 12-week trial (Raison et al. R. C.H. A.. the proliferation of new discoveries over the past several decades that link depression to immuneinflammatory processes.. Akpan.I.. Its basic premise that depression is an adaptive immune strategy (1) indicates that many behavioral features of depression may serve an adaptive purpose to help fight existing infections and avoid new ones. S. celecoxib has been found to block COX-2 enzymes as well as to reduce depression-like behaviors in laboratory animals (Guo et al. . Pharmacologic interventions that have established antimicrobial. Andréasson. American Psychiatric Association. also opens the door for a wide range of novel pharmacologic interventions in the clinical management of depression. would be expected. Anxiety 26... L. G. 1999.. the infection-defense hypothesis bears important clinical implications for the treatment and prevention of depression. For example. MohebbiRasa. and nutritional supplementation to correct for deficiencies in omega-3 fatty acids and vitamin D. and (2) points to the need for a fundamental shift in depression treatment that favors the primacy of investigating and remedying underlying infections or immune-compromising factors (both environmental and endogenous) that may be contributing to depression. (1997) that psychiatric patients tend to have higher rates of unrecognized and untreated physical illness than the rest of the population.S. Etanercept. B. Wildschiødtz. Acta Psychiatr. Behavior.. Yilmaz... Badcock. A putative role for cytokines in the impaired appetite in depression. Salehi. Avery. Relatedly. Depress. J. The anti-inflammatory cytokine IL-10 has also been identified as a potential target for antidepressant action. depressed individuals may benefit from taking heightened precautionary measures to reduce the risk of incurring further immune challenge. 147–152. 295–301.W. Behav. For example. chronic pain.I. Campbell. This again underscores the need to rule out infection or immune-related causes of depression prior to treatment. Sci. Anders et al. 2006. Neuropsychopharmacol. Underlying infections or immune disorders may be under-diagnosed. and naproxen may have antidepressant effects by way of their action as cyclooxygenase (COX)-2 inhibitors (Müller.. engaging in strategies to enhance immune function could potentially complement traditional anti-depressant therapies. N. 2006). 815–826. K. 2009). has demonstrated anti-inflammatory and anti-depressant effects in both human and animal studies (Pae et al. 2002). Washington. Darwinian models of depression: a review of evolutionary accounts of mood and mood disorders. may be simple and economical ways to help alleviate depressive symptoms. however. Anxiogenic-like effect of chronic corticosterone in the light-dark emergence task in mice.. as numerous studies show. a potential risk of using anti-inflammatory agents in the treatment of depression is that the suppression of immune function may mask existing infections or increase susceptibility to new ones.. Neurosci. Ghoreishi. in animal studies. interventions that aid the body’s natural ability to fight infections. ibuprofen. Erlanson-Albertsson. S.. also deserve greater attention for their potential role in the etiology of depression. World J. First. increased levels of circulating IL-10 have been found in both humans and animals receiving anti-depressant treatment (Kenis and Maes. 21. an underlying infection.. or other shared spaces may help to reduce the spread of pathogens that contribute to depression. and insufficient exercise—deserves more investigation as a possible approach to treating and preventing depression.. 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