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Depression Symptoms, Low-Grade Inflammatory Activity, and New Targets for Clinical Intervention
Depression Symptoms, Low-Grade Inflammatory Activity, and New Targets for Clinical Intervention Francis Lotrich he influential role of the “peripheral” inflammatory system on brain function and behavior is gaining increasing attention. Several groups have outlined proposals for how immune cells and cytokines might influence neurocognitive function and disorders, including major depressive disorder (MDD) (1–3). There is preliminary evidence for beneficial effects of nonsteroidal anti-inflammatory drugs (4), agents that block tumor necrosis factor-␣ activity (5), omega-3 fatty acids, and minocycline (an antibiotic that has some anti-inflammatory activity) (6) on mood disorder symptoms. The implications for diagnosis and targeting of treatment are evident. For starters, does the depression that is associated with increased inflammatory activity respond to different treatments than other types of depression? Who would most benefit from these alternative treatments? These questions might be particularly salient as people get older, because of the many changes that occur in the regulation of immune systems with age as well as an interaction between the inflammatory and monoaminergic systems. The report in this issue of Biological Psychiatry by Capuron et al. (7) provides some insight into how the inflammatory system might influence peripheral monoaminergic systems in older adults, one potential pathway for effects on brain function and behavior. First, many inflammatory cytokines are known to increase expression of indolamine deoxygenase (IDO), which is involved in tryptophan metabolism; and increased IDO activity can result in decreased serotonin, shunting the conversion of tryptophan to kynurenine (a glutamatergic compound). The authors found, consistent with this, that even when controlling for age, interleukin-6 (IL-6; an inflammatory cytokine in the peripheral circulation) and C-Reactive Protein (CRP) levels were positively associated with an increased ratio of kynurenine to tryptophan (Kyn/Trp). The experimental parallel to this is tryptophan depletion, which might affect mood and cognition. Second, inflammatory cytokines might also increase expression of guanosine-triphosphate-cyclohydrolase-1, which is a critical enzyme in the synthesis of either neopterin or tetrahydrobiopterin (BH4). Tetrahydrobiopterin is a cofactor for a number of enzymes, including tyrosine hydroxylase and nitric oxide synthase. In a finding consistent with this, IL-6 and CRP levels were correlated with increased neopterin and nitrite levels; and neopterin levels also strongly correlated with the Kyn/Trp ratio. Third, the authors did not measure BH4 directly but relied on the role of BH4 as a cofactor in the conversion of phenylalanine to tyrosine. Inflammatory markers were not associated with the ratio of phenylalanine to tyrosine (Phe/Tyr). However, this negative finding was complicated by the fact that BH4 can be very sensitive to oxidative stress (which is also often increased during inflammation), confounding interpretation of the peripheral Phe/Tyr ratio. Regardless, in the peripheral circulation, increased low-grade inflammatory activity (as indexed by elevated IL-6 and CRP) can be associated with increases in two separate pathways that influence monoaminergic metabolism (IDO
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From the University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania. Address correspondence to Francis Lotrich, M.D., Ph.D., Western Psychiatric Institute and Clinic, 3811 Ohara Street, Pittsburgh, PA 15213; E-mail: [email protected]. Received May 25, 2011; accepted May 25, 2011.
0006-3223/$36.00 doi:10.1016/j.biopsych.2011.05.022
and guanosine-triphosphate-cyclohydrolase-1 ). Whether these subtle changes in peripheral neurotransmitter precursors such as tryptophan and tyrosine causally influence brain function is an intriguing possibility. One unfortunate limitation of this study was that only .7% (n ⫽ 2) of the subjects had MDD (and only 14% had a lifetime history of depression)—the authors examined 284 subjects from an ongoing epidemiological cohort of 9294 older adults. The small MDD prevalence limited the power to correlate peripheral biomarkers with depression symptoms (or cognition). Nonetheless, in these subjects, some neuro-vegetative symptoms were cross-sectionally associated with inflammation, in particular poor appetite and fatigue. Thus, there was some evidence that a few symptoms on a 10-item depression rating scale associated with metabolites of the IDO pathway. There is already a pre-existing body of evidence that these peripheral biomarkers are associated with depression (8,9), providing further impetus and biological justification for prospectively examining these markers in mood and cognition—in cohorts at high risk for MDD or currently diagnosed with MDD. Moreover, there was a hint that these two pathways could differentially influence two different sets of neuro-vegetative symptoms, suggesting that in future studies we will likely need to measure more than just “inflammation.” The “peripheral” vasoconstrictor serotonin was discovered to play a part in the central nervous system over 60 years ago; and it is now evident that the “peripheral” inflammatory systems interact with the monoaminergic amines. For example, genetic differences in the serotonergic system might moderate the effect of inflammatory cytokines on behavior and mood (10). As the details of these interactions involving low-grade inflammatory activity are delineated, the opportunity to develop novel nonmonoaminergic interventions as well as fine-tune and target existing interventions is anticipated. Potential treatments that might benefit a subset of people include resveratrol, vitamins B6 and 12, nonsteroidal antiinflammatories, exercise and improved sleep, omega-3 fatty acids, minocycline and related medications, tumor necrosis factor-␣ and IL-6 antagonists, and moderators of the mitogen-associated protein kinase pathways. Peripheral biomarkers that might be plausibly used to track effectiveness or to target interventions include neopterin, Kyn/Trp, Phe/Tyr, nitrite, and IL-6. However, initial questions still include: Are these pathways simply associated with neurovegetative symptoms or with additional specific mood and cognitive deficits? Are these pathways associated with increased risk of conversion to MDD and/or more rapid progression of cognitive deficits (and thus targets for prevention)? And do these pathways identify individuals with different response to currently available antidepressant treatments?
This work was supported by the National Institute of Mental Health Grant R01MH090250. The author reports no biomedical financial interests or potential conflicts of interest. 1. Pollmacher T, Haack M, Schuld A, Reichenberg A, Yirmiya R (2002): Low levels of circulating inflammatory cytokines—Do they affect human brain functions? Brain Behav Immun 16:525–532.
BIOL PSYCHIATRY 2011;70:111–112 © 2011 Society of Biological Psychiatry
112 BIOL PSYCHIATRY 2011;70:111–112 2. Maes M (1995): Evidence for an immune response in major depression: A review and hypothesis. Prog Neuro-Psychopharmacol Biol Psychiatry 19:11–38. 3. Miller AH, Raison CL (2006): Cytokines, p38 MAP kinase and the pathophysiology of depression. Neuropsychopharmacology 31:2089 –90. 4. Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, et al. (2009): Clinical trial of adjunctive celecoxib treatment in patients with major depression: A double blind and placebo controlled trial. Depress Anxiety 26:607– 611. 5. Krishnan R, Cella D, Leonardi C, Papp K, Gottlieb AB, Dunn M, et al. (2007): Effects of etanercept therapy on fatigue and symptoms of depression in subjects treated for moderate to severe plaque psoriasis for up to 96 weeks. Br J Dermatol 157:1275–1277. 6. Pae CU, Marks DM, Han C, Patkar AA (2008): Does minocycline have an antidepressant effect? Biomed Pharocother 62:308 –311.
www.sobp.org/journal
Commentary 7. Capuron L, Schroecksnadel S, Feart C, Aubert A, Higueret D, BarbergerGateau P, et al. (2011): Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: Role in neuropsychiatric symptoms. Biol Psychiatry 70:175–182. 8. Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, et al. (1994): Increased neopterin and interferon-gamma secretion and lower availability of L-Tryptophan in major depression: Further evidence for an immune response. Psychiatry Res 54:143–160. 9. Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D (2002): Neopterin production, tryptophan degradation, and mental depression—What is the link? Brain Behav Immun 16:590 –595. 10. Lotrich FE, Ferrell RE, Rabinovitz M, Pollock BG (2009): Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism. Biol Psychiatry 65:344 –348.
T
From the University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania. Address correspondence to Francis Lotrich, M.D., Ph.D., Western Psychiatric Institute and Clinic, 3811 Ohara Street, Pittsburgh, PA 15213; E-mail: [email protected]. Received May 25, 2011; accepted May 25, 2011.
0006-3223/$36.00 doi:10.1016/j.biopsych.2011.05.022
and guanosine-triphosphate-cyclohydrolase-1 ). Whether these subtle changes in peripheral neurotransmitter precursors such as tryptophan and tyrosine causally influence brain function is an intriguing possibility. One unfortunate limitation of this study was that only .7% (n ⫽ 2) of the subjects had MDD (and only 14% had a lifetime history of depression)—the authors examined 284 subjects from an ongoing epidemiological cohort of 9294 older adults. The small MDD prevalence limited the power to correlate peripheral biomarkers with depression symptoms (or cognition). Nonetheless, in these subjects, some neuro-vegetative symptoms were cross-sectionally associated with inflammation, in particular poor appetite and fatigue. Thus, there was some evidence that a few symptoms on a 10-item depression rating scale associated with metabolites of the IDO pathway. There is already a pre-existing body of evidence that these peripheral biomarkers are associated with depression (8,9), providing further impetus and biological justification for prospectively examining these markers in mood and cognition—in cohorts at high risk for MDD or currently diagnosed with MDD. Moreover, there was a hint that these two pathways could differentially influence two different sets of neuro-vegetative symptoms, suggesting that in future studies we will likely need to measure more than just “inflammation.” The “peripheral” vasoconstrictor serotonin was discovered to play a part in the central nervous system over 60 years ago; and it is now evident that the “peripheral” inflammatory systems interact with the monoaminergic amines. For example, genetic differences in the serotonergic system might moderate the effect of inflammatory cytokines on behavior and mood (10). As the details of these interactions involving low-grade inflammatory activity are delineated, the opportunity to develop novel nonmonoaminergic interventions as well as fine-tune and target existing interventions is anticipated. Potential treatments that might benefit a subset of people include resveratrol, vitamins B6 and 12, nonsteroidal antiinflammatories, exercise and improved sleep, omega-3 fatty acids, minocycline and related medications, tumor necrosis factor-␣ and IL-6 antagonists, and moderators of the mitogen-associated protein kinase pathways. Peripheral biomarkers that might be plausibly used to track effectiveness or to target interventions include neopterin, Kyn/Trp, Phe/Tyr, nitrite, and IL-6. However, initial questions still include: Are these pathways simply associated with neurovegetative symptoms or with additional specific mood and cognitive deficits? Are these pathways associated with increased risk of conversion to MDD and/or more rapid progression of cognitive deficits (and thus targets for prevention)? And do these pathways identify individuals with different response to currently available antidepressant treatments?
This work was supported by the National Institute of Mental Health Grant R01MH090250. The author reports no biomedical financial interests or potential conflicts of interest. 1. Pollmacher T, Haack M, Schuld A, Reichenberg A, Yirmiya R (2002): Low levels of circulating inflammatory cytokines—Do they affect human brain functions? Brain Behav Immun 16:525–532.
BIOL PSYCHIATRY 2011;70:111–112 © 2011 Society of Biological Psychiatry
112 BIOL PSYCHIATRY 2011;70:111–112 2. Maes M (1995): Evidence for an immune response in major depression: A review and hypothesis. Prog Neuro-Psychopharmacol Biol Psychiatry 19:11–38. 3. Miller AH, Raison CL (2006): Cytokines, p38 MAP kinase and the pathophysiology of depression. Neuropsychopharmacology 31:2089 –90. 4. Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, et al. (2009): Clinical trial of adjunctive celecoxib treatment in patients with major depression: A double blind and placebo controlled trial. Depress Anxiety 26:607– 611. 5. Krishnan R, Cella D, Leonardi C, Papp K, Gottlieb AB, Dunn M, et al. (2007): Effects of etanercept therapy on fatigue and symptoms of depression in subjects treated for moderate to severe plaque psoriasis for up to 96 weeks. Br J Dermatol 157:1275–1277. 6. Pae CU, Marks DM, Han C, Patkar AA (2008): Does minocycline have an antidepressant effect? Biomed Pharocother 62:308 –311.
www.sobp.org/journal
Commentary 7. Capuron L, Schroecksnadel S, Feart C, Aubert A, Higueret D, BarbergerGateau P, et al. (2011): Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: Role in neuropsychiatric symptoms. Biol Psychiatry 70:175–182. 8. Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, et al. (1994): Increased neopterin and interferon-gamma secretion and lower availability of L-Tryptophan in major depression: Further evidence for an immune response. Psychiatry Res 54:143–160. 9. Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D (2002): Neopterin production, tryptophan degradation, and mental depression—What is the link? Brain Behav Immun 16:590 –595. 10. Lotrich FE, Ferrell RE, Rabinovitz M, Pollock BG (2009): Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism. Biol Psychiatry 65:344 –348.