Many instances of major depression are accompanied by evidence of elevated inflammatory cytokines. Data from animal models and human studies indicate a role for these cytokines in the etiology and development of depression.
A common example is the depression that occurs during interferon-alpha therapy (IFN-alpha). This model of depression is improving our understanding of why some people are more vulnerable to depression; how to potentially mitigate this vulnerability; and, thus, how to potentially prevent depression. This has led to improved strategies for managing patients who will be receiving IFN-alpha treatment.
Moreover, the role of various neurotransmitter systems in IFN-alpha major depressive disorder (MDD) is being delineated, leading to a better understanding of how cytokines might trigger depression. Because it is likely that inflammatory cytokines are also involved in other instances of depression (inflammatory cytokine-associated depression), this may provide an opportunity for translating the ongoing IFN-alpha MDD research and work using animal models into novel strategies for the prevention and treatment of mood disorders.
Inflammation in Major Depression
The biological implications of a bi-directional relationship between inflammation and depression are becoming increasingly appreciated.1 During a major depressive episode, various immune-related changes have been observed, including increased helper-1 T cells, increased monocytes and macrophages, lowered regulatory T cells, and hyperactive responses to ex vivo stimulation with mitogens.
Moreover, many cytokines regulate the immune response, including the interleukins (numbered 1 through 37), interferons (alpha, beta, gamma, delta), tumor necrosis factors, growth factors, and cytokine modulators such as the soluble interleukin-1 (IL-1) receptor antagonist.
Of these, systemically circulating levels of both IL-6 and tumor necrosis factor-alpha (TNF-alpha) have been the most consistently elevated in depressed patients, as noted in a recent meta-analysis of 24 studies.2 Postmortem studies of brain tissue provide further evidence for increase of inflammation, apoptosis, and oxidative stress in people with depression.3
It is possible that the same physiologic trigger (eg, psychosocial stress) could result in both depression and immune changes, which would explain their co-occurrence. Stress, glucocorticoids, and poor sleep all modulate inflammatory responses. However, there is also accruing evidence that the immune system may actually have causal influences on development of depression.
Consistent with this, both IL-1beta and IL-1 receptor antagonist levels may predict the future incidence of a major depressive episode.4 Additionally, in patients treated with IFN-alpha, about 15% to 40% soon become depressed. Using time-lagged analyses of prospective assessments of people being treated with IFN-alpha, increases in IL-6 precede increased depression, which in turn further increases IL-6.5 Thus, individuals vulnerable to depression have a feed-forward loop linking depression and IL-6.
Conversely, those who did not develop depression did not have elevated IL-6 to begin with, nor did IL-6 further increase during treatment with IFN-alpha.5 This type of finding was also recently observed in adolescents for whom elevated IL-6 levels forecast depression 6 months later (primarily in those who were vulnerable because of childhood adversity).6 The authors concluded that childhood adversity may promote amplified feed-forward signaling between the peripheral immune system and central affect regulation.
Role of Inflammatory Cytokines
One of the first cytokines discovered, IL-1beta, has an influence on depression-like behaviors in rodents.7 Some of IL-1beta’s behavioral effects include diminished operant responding for rewards (an “anhedonia-like” behavior) and impaired social interaction.8 Additionally, chronic IFN-alpha treatment (as well as other cytokines) can result in decreased escape attempts (“amotivation-like” behavior) when mice are suspended by their tail or isolated in a swimming tank.9
The adverse behavioral effect of inescapable shocks can also be blocked by treatment with an IL-1 receptor antagonist.10 This suggests that the amotivational syndrome sometimes called “learned helplessness” may likewise be the result of increased IL-1. In fact, many of the behavioral effects of stress can be attenuated by blocking the inflammation-related pathways.11
The field of depression research is now well-situated to use findings from inflammation-related behaviors in animal models to inform clinical treatment research on depression. As just one example, a critical intracellular influence on inflammatory cytokine production is nuclear factor-kappa B (NF-kappaB), which is a critical mediator of stress-impaired neurogenesis and depressive behavior,12 and possibly a potential treatment target.
Depressed states can be triggered by experimental cytokine administration in humans. In fact, injection of bacterial wall endotoxins, the Salmonella typhi vaccine, or the typhoid vaccine all transiently increase IL-6, IL-1, and/or TNF-alpha, along with transiently worsened mood.13 Thus, a potentially viable subtype of depression in humans is “inflammatory cytokine-associated depression” (ICAD).
Depression secondary to a medical illness may be a type of ICAD, as many cytokines are associated with depression when it occurs during coronary disease, infectious illness, dermatitis, and kidney disease. Moreover, the oft-repeated observation that IL-6 and TNF-alpha and possibly other cytokines are elevated even in depressed people without medical illness2 supports the hypothesis that ICAD could be a reasonably common MDD subtype.
Depression During IFN-Alpha Treatment
One clear and common example of ICAD is the major depression that develops during treatment with IFN-alpha, sometimes referred to as inteferon-induced major depressive disorder (IFN-MDD). IFN-MDD can include suicidal ideation, crying, irritability, anxiety, amotivation, social withdrawal, and anhedonia. Depending on the baseline characteristics of the individuals receiving treatment, how depression is assessed, and the existence of co-occurring mental health interventions, the incidence can range from 15% to more than 40% within a few months of treatment.14 The effect is dose-dependent and is usually reversible with discontinuation of IFN-alpha.
Because of the high incidence of depression over only a few months, there is also tremendous potential to use IFN-MDD as a paradigmatic tool for prospectively examining the pathophysiology of ICAD. There are also immediate clinical implications for those who suffer from chronic infection with hepatitis C virus.
Because of the problematic impact of depression during IFN-alpha treatment (therapy is typically 24 or 48 weeks long), the psychiatrist is often asked to provide “psychiatric clearance.” Also, many patients seeking treatment for hepatitis C virus already have pre-existing mental health problems. It is therefore generally recommended that patients be assessed to ensure that alcohol use is minimized (ideally 3 to 6 months of sustained sobriety),15 that any pre-existing mood disorders and anxiety disorders are diagnosed and effectively treated, and that psychotic disorders are adequately stabilized before treatment begins.
A pretreatment assessment should additionally identify and address any potential barriers to psychiatric care (eg, financial or social). The patient and family should be educated about individual risk for developing depression during IFN-alpha treatment. Ensuring ongoing monitoring and follow-up is essential, as is prompt communication between the psychiatrist and hepatologist. With these components in place, and if pre-existing psychiatric disorders are managed, then outcomes can be similar to those observed in patients without mental illness.16
Nonetheless, many patients without any history of prior mental illness can develop neuropsychiatric symptoms during IFN-alpha therapy.17 Patients should be educated about these other side effects. Of this patient group, a large minority (up to 25%) develops a syndrome comprised of labile anger, irritability, and/or hostility.18–20 Genetic studies indicate that this labile-anger syndrome is distinct from depression.21 However, little is known about effectively treating labile anger or about whether it could be related to subsyndromal mania. This syndrome therefore remains a clinical challenge, both in terms of diagnosis and treatment.
Fatigue is likewise distinct from depression and can be incapacitating. Small open-label trials of modafinil, methylphenidate, and exercise have shown modest benefits. However, apart from directly addressing any anemia and/or hypothyroidism, the treatment of fatigue likewise remains challenging.
Diminished cognitive processing speed is another side effect of IFN-alpha therapy. When these cognitive side effects are severe enough or when delirium occurs, dose reduction or discontinuation is typically necessary.
Insomnia can also occur. Poor sleep may respond to nonpharmacologic treatments (eg, sleep hygiene and relaxation techniques); antihistamines; benzodiazepine receptor agonists; or antidepressant treatment. The relative efficacy of these approaches in this population awaits further clarification.
Finally, antipsychotic medications are useful for the psychosis that can occur in less than 0.1% of patients. Of relevance for understanding depression, these various side effects can be either completely distinct entities or can partially overlap.22
Prevention of Depression in IFN-Alpha Therapy
Depression continues to be a common source of morbidity, and selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment for IFN-MDD Most patients (as many as 85%) respond well to SSRI treatment.23 Alternatives to SSRIs include other classes of anti-depressants (mostly supported by case reports) or electroconvulsive therapy. As the risk for depression relapse remains high immediately following the discontinuation of IFN-alpha treatment,24 any antidepressants used to successfully treat IFN-MDD should be continued for a period following the completion of IFN-alpha therapy (generally at least 3 to 6 months is recommended).
With the goal of preventing IFN-MDD, there have now been several prophylactic trials of SSRIs, although the initial studies were limited in size and power. In an early meta-analysis of open-label studies, 15 of 97 (15%) patients receiving SSRIs prior to starting IFN-alpha developed IFN-MDD compared with 36 of 99 (36%) not taking SSRIs.14 Limiting the meta-analysis to randomized controlled studies, only 10 of 55 (18%) patients treated with SSRIs developed IFN-MDD compared with 21 of 68 (31%) taking placebo.14 In these studies, SSRI use reduced the incident risk of IFN-MDD by about half.
There have since been larger studies, including a multisite European study that examined patients specifically excluded from having a history of MDD and with baseline Montgomery-Asberg Depression Rating Scale scores of less than 3.17 Of those randomized to SSRI pretreatment (n = 90), 8% developed MDD compared with 18% of those randomized to placebo (n = 91).17
Again, the incidence of depression was approximately halved by SSRI pretreatment. Although only 10% of patients may have benefited from SSRI pretreatment, this information can now be included in risk-benefit discussions with patients at high risk for ICAD.
The resilience of most people (the majority who do not develop IFN-MDD even without SSRI pretreatment) has prompted the search for clinically modifiable risk and protective factors. Of course, elevated baseline depression symptoms are clearly associated with the development of subsequent IFN-MDD. Similarly, increased acute reactivity of the hypothalamic-pituitary-adrenal (HPA) axis can be modified with antidepressants, is known to be associated with MDD, and has been associated with increased vulnerability to IFN-MDD.25
It is plausible that either elevated depression scores and/or increased HPA reactivity could be used to target individuals for SSRI pretreatment.
Insomnia prior to IFN-alpha treatment may be an important and major modifiable risk factor.5,19 Patients who had scores higher than 10 on the Pittsburgh Sleep Quality Index were 10 times more likely to subsequently develop IFN-MDD than patients who slept well, even when controlling for other depression symptoms.19 Thus, treating existing sleep problems has great potential to prevent depression.
What is not yet known is which aspect of sleep quality may be an important target for preventive therapy. For example, whether it is the number of hours slept, percent of rapid eve movement (REM) sleep, number of awakenings and restlessness, percent of deep slow wave sleep, or something else is unknown. Benzodiazepine receptor agonists may decrease restlessness and increase sleep time but at the expense of decreasing slow wave sleep.
Determining how best to improve sleep as a targeted approach for preventing depression (in particular, IFN-MDD) thus remains on ongoing need.
There is also evidence that an increased ratio of omega-6 to omega-3 fatty acids may adversely influence risk for IFN-MDD. Also, elevated IL-6 and an associated IL-6 gene polymorphism are both predictive of subsequent IFN-MDD.5,26 IL-6 may be influenced by diet, the amount of omega-3 fatty acids in the diet,27 and/or exercise. As diet is a feasible intervention target, this may offer a safe approach toward depression prevention.27
Other targets for attention include social isolation and neuroticism,20 either of which may be addressed with psychosocial interventions. Future studies are now necessary to examine whether pretreatments that ameliorate any of these specific vulnerabilities can prevent IFN-MDD. This line of clinical research will be immediately useful to those who are prescribed IFN-alpha, but may also be an initial step in preventing other instances of ICAD and even possibly the targeted prevention of MDD in general.
Neurotransmitters and IFN-MDD
A number of neurotransmitter systems are influenced by cytokines, including serotonin (5-HT).28 In fact, genetic polymorphisms within the 5-HT system have been associated with vulnerability to IFN-MDD.29 Also, low-grade inflammation and IL-6 can result in increased indolamine-2,3-dioxygenase (IDO) activity, which results in increased metabolism of tryptophan, thereby limiting tryptophan’s availability for conversion to 5-HT. Compounding inflammation-induced depletion of 5-HT is the fact that inflammatory cytokines may also increase 5-HT release at synapses, increase expression of the 5-HT reuptake transporter, and alter expression of both 5-HT1A and 5-HT2 receptors.28
In addition, imaging of the brain implicates basal ganglia regions for several IFN-alpha effects.30 It is therefore likely that some of the behavioral signs and symptoms induced by cytokines (eg, possibly fatigue and amotivation) are the result of changes in dopamine transmission.
Cytokines can also affect synaptic plasticity and growth factors, glucocorticoid function, glutamatergic signaling and glutamatergic compounds such as kynurenic acid, and circadian rhythms.28 The parallel prospective studies that are occurring in both human and animal models are helping to delineate the neuro-chemical and anatomic pathways that are critical for depression development.
The possibility that ICAD is an important subtype of MDD opens up the possibility that there could be a variety of new treatment targets for ICAD. Such examples include cytokine-based medications being investigated or used for inflammatory disorders, such as IL-1 antagonists; the anti-inflammatory cytokine IL-10; the soluble IL-4 receptor; soluble receptors for TNF-alpha or TNF-alpha antagonists; intracellular targets of inflammatory activity such as mitogen-associated protein kinase inhibitors or IL-1–associated kinase-4 inhibitors; omega-3 fatty acids; or minocycline (which has potential anti-inflammatory and antidepressant effects). All of these various approaches have the potential to modulate the effect of inflammation and thereby treat or prevent ICAD.28
The increasing recognition of IFN-MDD has led to advances over the past decade. Specific clinical recommendations based on recent clinical research have been reviewed here. These clinical studies are likely to have immediate impact for patients who need to be treated with IFN-alpha.
Also, the possibility that there may be other instances of endogenous ICAD could have consequences for biological subtyping of MDD and translating findings from homologous animal models into novel, non-monoaminergic approaches for ICAD treatment and prevention.
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- Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446–457. doi:10.1016/j.biopsych.2009.09.033 [CrossRef]
- Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry. 2011;16(7):751–762. doi:10.1038/mp.2010.52 [CrossRef]
- van den Biggelaar AHJ, Gussekloo J, de Craen AJM, et al. Inflammation and interleu-kin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age. Exp Gerontol. 2007;42(7):693–701. doi:10.1016/j.exger.2007.01.011 [CrossRef]
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- Miller GE, Cole SW. Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. Biol Psychiatry. 2012;72:34–40. doi:10.1016/j.biopsych.2012.02.034 [CrossRef]
- Anisman H. Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci. 2009;34(1):4–20.
- Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. 2002;25(3):154–159. doi:10.1016/S0166-2236(00)02088-9 [CrossRef]
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- Hosoda S, Takimura H, Shibayama M, et al. Psychiatric symptoms related to interferon therapy for chronic hepatitis C: clinical features and prognosis. Psychiatry Clin Neurosci. 2000;54:565–572. doi:10.1046/j.1440-1819.2000.00754.x [CrossRef]
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