Are Chronic Inflammation and its Metabolic Counterpart, Insulin Resistance, the Common Denominators for All Chronic Behavioral and Neurodegenerative Disorders? – A Review of the Evidence – Part V


As you might imagine, despite the large volume of research supporting the idea that depression is an inflammatory illness, many in both the clinical and academic communities will point to various manifestations and subtleties of the average case of depression as evidence that, for this patient, the depression can’t be inflammatory.  Therefore, in this installment I would like to address some of these qualifiers used by the naysayers to support their belief that depression can’t be an inflammatory illness and present evidence that, almost invariably, these qualifiers have an inflammatory basis.


As I mentioned previously in this series, there is ample evidence that SSRIs, in addition to their impact on serotonin metabolism, have anti-inflammatory activity.  However, despite this evidence, the general consensus still supports the idea that, since SSRIs are so effective, suboptimal serotonin metabolism must be the main underlying cause of depression.  Interestingly, this argument might hold more weight in terms of downplaying the inflammatory hypothesis of depression except for one major flaw.  When considering major depressive disorder (MDD), SSRIs have demonstrated questionable efficacy at best.  In “Examining the role of neuroinflammation in major depression” by Furtado and Katzman (1) the following is noted:

“Although the prevalence of MDD continues to rise worldwide, many treatment options for patients remain ineffective.  Greater than half of all MDD patients receiving first-line treatments, and approximately two-thirds of those receiving Selective Serotonin Reuptake Inhibitors (SSRIs), do not achieve remission.”

Could the reason for this lack of effectiveness be the presence of inflammation and its functional counterpart that I discussed in part IV, glucocorticoid resistance?  To answer this question, consider the following quote from the Furtado and Katzman (1) paper:

“A study conducted by Fitzgerald et al. evaluated the sensitivity of glucocorticoid receptors (GR) in treatment resistant MDD patients (n = 19) versus healthy controls (n = 38).  Treatment resistance in this study was defined as a failure of at least 6 weeks of antidepressant therapy (venlafaxine, fluoxetine, citalopram, moclobemide, mitrazepine, sertraline, imipramine, reboxetine), such that their HAM-D scores did not decrease by 50% or greater.  MDD patients exhibited significantly greater TNF-α (22.02 ± 3.62 pg/mL vs. 12.10 ± 2.56 pg/mL: p = 0.03) and IL-6 (1.18 ± 0.12 pg/mL vs. 0.73 ± 0.11 pg/mL; = 0.01) concentrations, versus controls.”

“O’Brien et al. further demonstrated an elevated cytokine profile in depressed patients resistant to SSRI treatment.  Patients (= 28) meeting DSM-IV criteria for MDD who had failed a 6 week course of an SSRI (fluoxetine, paroxetine, or citalopram at a minimum of 20 mg daily), were compared to a group of previously SSRI resistant depression patients (= 16), who were now euthymic following a switch or the addition of lithium to the SSRI, as well as healthy controls (n = 24).  Measurements of IL-6, IL-8, IL-10, sIL-6R, and TNF-α were collected and analyzed, in which SSRI-resistant patients had significantly greater levels of proinflammatory cytokines IL-6 (p=0.01) and TNF-α (p =0.004) compared to healthy controls.”

As you can see, there is a very high correlation between SSRI failure in MDD patients, which is very common, and the presence of significant chronic inflammation as expressed by higher than normal pro-inflammatory cytokines.

What about the “other side of coin” that I mentioned previously, cortisol imbalances in MDD patients who are resistant SSRIs?  Furtado and Katzman (1) address this relationship by discussing a study by Markopoulou et al:

“Plasma cortisol levels, DHEA, and their molar ratio was assessed in patients (n = 28) with treatment resistant depression (TRD), as defined by failure to respond to two or more adequate therapeutic trials, and compared to healthy controls (n = 40).  Samples were collected at 0900 h and repeated following inpatient treatment to a subgroup of 21 patients who had followed-up.  Baseline cortisol levels were significantly increased in TRD patients vs. controls, however DHEA levels did not differ.  The ratio of baseline cortisol/DHEA was also significantly increased in TRD patients.”

What about another excellent indicator of chronic inflammation, high sensitivity C-reactive protein (hsCRP)?  Based on what has been presented above, it would be logical to expect that depression patients with elevated hsCRP levels would not respond well to SSRI treatment.  This is indeed the situation since the authors point out that at levels of hsCRP that are 5 mg/L and higher the treatment success rate with infliximab begins to drop compared to placebo.  In another study on CRP and major depressive disorder (MDD) Furtado and Katzman (1) reported the following:

“…women with MDD were twice as likely compared with healthy controls to have CRP levels about the 75thpercentile.” 


Another reason why there is resistance to the idea that depression may be an inflammatory disorder was revealed to me in several discussions with health care practitioners where it was apparent that their vision of what constitutes an inflammatory disease, which is a visibly inflamed organ as seen with diseases such as rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, etc., is not seen with depression.  As the argument goes “The brain is not visibly or grossly inflamed in depressed patients.  Therefore, how can inflammation cause depression?”  What is my answer to this?  First, as I suggested in previous installments of this series, the key issue is not that the brain is grossly inflamed but the fact that systemic inflammation has an adverse impact on metabolism of the hormones and amino acids that are involved in the creation and utilization of neurotransmitters involved with the determination of behavior.  I will discuss this in more detail shortly in my discussion that follows on  cortisol and my in depth discussion of the kynurenine pathway.

However, before I discuss the impact of inflammation on neurotransmitter metabolism, I would like to address this qualifier from an evolutionary, allostatic point of view.  This point of view would suggest that inflammation-induced depression must exist because it is a logical response to an adverse set of circumstances.  Or, more precisely, it is in the best interest in terms of long-term survival to become depressed whenever the body becomes significantly inflamed.  This evolutionarily adaptive rationale underlying the existence of depression whenever inflammation exists was explored in the paper “Inflamed moods: A review of the interactions between inflammation and mood disorders” by Rosenblat et al (2).  The authors’ discussion of this rationale begins with the following:

“Hart was the first to postulate a reason for psychological and behavioral symptoms resulting from an inflammatory response.  He argued that the behavioral symptoms associated with inflammation or sickness was ‘not a maladaptive and undesirable effect of illness but rather a highly organized strategy that is at times critical to the survival of the individual if it were living in the wild state.’  He postulated that animals and humans alike would benefit from neuro-vegetative symptoms such as lethargy, decreased appetite, decreased mood, increased sleep, decreased interest in activities and exploration and decreased sexual activity to allow for the organism to devote their time and energy to healing and protection from future attacks.  This phenomenon later became referred to as ‘sickness behavior’.  On a population level, the behavior may also be beneficial to prevent the spread of infectious diseases through sick individuals’ propensity to have neuro-vegetative symptoms leading to the avoidance of interaction with others.”

Of course, as I have mentioned often concerning the allostatic model of illness that suggests all symptomatology is reflective of a response to an adverse environment, what was discussed above is only going to be beneficial to the individual and the society at large in the short term.  From a long term point of view, the outcome, for which the term “allostatic load” has been used, is largely detrimental.  As noted below by Rosenblat et al (2), this is certainly true for the depressive symptoms discussed above:

“While behavioral symptoms of inflammation may be helpful in the setting of acute infection, there are many cases when these symptoms may be detrimental.  For example, in cases of patients of chronic inflammatory diseases unrelated to infection, such as auto-immune disorders, cardiovascular disease, obesity and diabetes; comorbid mood symptoms do not appear to serve an evolutionary benefit, but seem to instead worsen symptomatology.”

With the above in mind, the authors state:

“Taken together, the induction of mood symptoms by inflammation may be advantageous in certain circumstances, such as acute infection; however, in many other circumstances such as chronic inflammatory disorders, these symptoms may be a vestigial nuisance, producing more harm than good.  Furthermore, if the psychological symptoms of medical illness, i.e., ‘sick behavior,’ are mediated by an inflammatory response, blunting the inflammatory response may aid in decreasing the psychological symptoms independent of the resolution of the medical illness.”

How does inflammation adversely affect neurotransmitter metabolism?  There are two primary ways.  One, which I discussed in part IV of this series, has to do with cortisol metabolism.  Below you will find a quote from the Rosenblat et al (2) paper that provides an excellent summary of the research I discussed previously:

“…replicated studies have demonstrated that cytokines such as IL-1, IL-6, TNF-α and IFN-α, activate the HPA axis, increasing levels of corticotrophin releasing hormone (CRH), adrenocorticotrophic hormone (ACTH) and cortisol.  This effect is a well-established component of the generalized stress response induced by inflammation.  Furthermore, these cytokines have been documented to decrease the expression, translocation and downstream effects of glucocorticoid receptors, thereby blunting the negative feedback loop of the HPA axis allowing for further elevation of cortisol levels.  Repeated stimulation of the inflammatory system has been shown to disproportionately increase HPA axis activity compared to the usual response.  Therefore, in an inflammatory state, cortisol levels are elevated through cytokine stimulation of the HPA axis and by impaired HPA negative feedback self-regulation.”

Of course, traditional thinking suggests that this elevation in cortisol will reduce levels of inflammatory mediators.  However, this is generally true only in the short term.  With long term elevations in inflammation and cortisol, the anti-inflammatory effects of cortisol are diminished:

“…while serum cortisol levels are measured as high in response to cytokines, the actual anti-inflammatory effect is low because of the cytokine induced decrease in glucocorticoid receptor synthesis, translocation, and binding.”

However, this chronically elevated cortisol has another metabolic impact that prolongs mood disorders besides the lack of anti-inflammatory activity.  It also, affects the metabolism of tryptophan, the amino acid precursor of serotonin, by diverting tryptophan away from serotonin production and towards the kynurenine pathway – which I have discussed previously in many newsletters and will discuss again in detail shortly.  In the quote below, Rosenblat et al (2) discuss the impact of elevated cortisol on tryptophan and cortisol metabolism:

“…elevated glucocorticoid levels (endogenous or exogenous) have been shown by many investigators to induce mood symptoms.”

In addition:

“…it has been shown that cortisol increases hepatic tryptophan 2,3-dioxygenase (TDO) activity, a potent catabolic enzyme of tryptophan, therefore leading to tryptophan depletion thereby decreasing serotonin synthesis and increasing levels of kynurenine, kynurenic acid and quinolinic acid.”

Of course, as I have also mentioned previously and will discuss again, cortisol via its upregulation of TDO is not the only way tryptophan is diverted away from the production of serotonin and towards the kynurenine pathway.  Inflammatory mediators also have a direct impact via the upregulation of the enzyme indoleamine 2,3-dioxygenase (IDO):

“Cytokines, more specifically IL-2 and IFN, have been shown to directly increase the enzymatic activity of indoleamine 2,3-dioxygenase (IDO) which increases the conversion of tryptophan to kynurenine and consequently decrease the production of serotonin.  The depletion of tryptophan and subsequent decrease in serotonin production is a well-established feature of mood disorders pathophysiology.  Moreover, tryptophan catabolites, namely kynurenine, kynurenic acid and quinolinic acid have been shown to independently induce depressive and anxiety symptoms.”

With the above in mind, Rosenblat et al (2) conclude:

“Taken together, inflammatory cytokines act on multiple levels to greatly decrease the levels of serotonin by decreasing serotonin production and increasing serotonin degradation.”


As I hope I have demonstrated, depression is more than just an issue of aberrant serotonin metabolism, as has been suggested by the allopathic community for years.  True, serotonin is involved.  However, concluding that, just because serotonin is involved in depression, it is the only important factor when considering depression is like saying that just because a violin is needed to play Beethoven’s 9th Symphony means that Beethoven’s 9th Symphony can be played just with a violin.  Of course, as we all know, while violins are necessary, a choir is also necessary to perform Beethoven’s 9th Symphony as written.  Depression is the same.  Yes – serotonin is important when considering depression.  But to truly understand depression and create better clinical outcomes than what have been demonstrated with SSRIs, we need to understand that depression is not only more than just an issue of serotonin imbalances but more than just an issue of neurotransmitter imbalances in general.  Why do I mention “neurotransmitter imbalances in general?”  As most of you know, there are many in the functional and alternative medicine community who feel that the answer to all mood and behavioral disorders lies almost exclusively with measurement of neurotransmitters, mainly via the urine, and optimization of neurotransmitter levels using amino acid, herbal, and micronutrient supplementation.  While feedback suggests that this approach to mood and behavioral disorders has demonstrated efficacy, feedback also suggests that efficacy could be even better if advocates of this approach, like the allopaths who advocate SSRIs, both kept an eye on serotonin and all the other neurotransmitters and vastly expanded their view of the neurophysiological realm and truly looked at all that lies beyond neurotransmitters.

Hopefully, I have made a strong case for the hypothesis that one of the main phenomena that lies beyond the horizon of neurotransmitters that we must consider to truly understand depression is the interesting and intimate interrelationship between inflammation and cortisol metabolism.  In addition, I hope I have also made a strong case for the idea that neurotransmitter physiology and inflammatory/cortisol physiology are not isolated, unrelated contributors to depression.  Rather, they are intimately related.  How are they related, specifically?  For me, this question can be answered with a simple yet profound phrase I have referred to repeatedly:

The kynurenine pathway

Throughout this series I have been providing overviews of the neurophysiology of the kynurenine pathway not only in relation to depression but all neurodegenerative, mood and behavioral disorders.  Now, I would like to examine the kynurenine pathway in depth and its relationship to inflammation and cortisol in order to demonstrate the potential when knowledge of this phenomenon is combined with what we currently know about neurotransmitters and their optimization with pharmaceuticals and/or natural substances.  What is this potential?  For me, clinical outcomes will be realized, even in complicated cases, that could not even be imagined when, as is typical, each is considered independent of each other.


To begin this exploration of the kynurenine pathway, I would first like to review a paper written in 1969 by the architects of the “serotonin hypothesis” that was introduced in this paper and directly led to the development of SSRIs, the multi-billion dollar industry revolving around these drugs, and even the alternative and functional medicine approaches to depression that revolve primarily around neurotransmitter manipulation.  In “Intensification of the central serotonergic processes as a possible determinant of the thymoleptic effect” by Lapin and Oxenkrug (3) the following is stated in the abstract:

“Psychic depression may result from deficiency in brain serotonin.  It is suggested that in depression the production of tryptophane pyrrolase by the liver is stimulated by raised blood-corticosteroid levels.  As a result of the metabolism of tryptohane is shunted away from serotonin production, and towards kynurenine production.  Blood-corticosteroid levels are raised in depression as a consequence of excitement of the amygdaloid complex, on which serotonin is normally an inhibitory influence.  Thus, whatever the order of events, a vicious circle is set up.  It is suggested that the actions of the various antidepressant treatments in use have a common mechanism – namely the intensification of the central serotonergic processes.  The thymoleptic action of imipramine-like tricyclic antidepressants results from potentiation of serotoninergic effects on the brain; these effects include inhibition of the amygdala, which suppresses central mechanisms of stress normally manifested in anxiety, tension, and fear.  The mood-elevating component of the antidepressant actions of monoamine-oxidase inhibitors and of electroconvulsive therapy is related to the increase in brain serotonin levels.”

Then, in the last paragraph of the paper, the authors state:

“This ‘serotonin hypothesis’ requires further investigation.”

Of course, as we all know, “further investigation” indeed occurred with the development of the multi-billion dollar SSRI-focused antidepressant industry.   It is also interesting and not surprising that, given all the mentions of serotonin in the above text, starting with the first sentence of the abstract, both clinicians and developers of pharmaceutical and natural products meant to address depression have focused on serotonin.  However, is this what the authors of the paper intended?  A paper written 40 years later by one of the original authors, Gregory Oxenkrug, entitled “Tryptophan-kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: The serotonin hypothesis revisited 40 years later” (4) suggests that the answer is no.  As you will see from the following quote in this paper, the authors intended the focus to be on the second sentence of the above abstract from the 1969 paper that suggests that the central issue in depression is disturbances in tryptophan metabolism:

“Although often referred to as “serotonin hypothesis,’ the 1969 Lancet paper proposed disturbances of tryptophan (TRY) metabolism, i.e., the shunt of TRY from serotonin (5-HT) synthesis to kynurenine (KYN) formation, as a major etiological factor of depression.

Oxenkrug (4) then states the following that suggests his primary emphasis in the 1969 paper was the kynurenine pathway and not just serotonin:

“The discovery of neurotropic activity of kynurenines emphasized the increased formation of kynurenines as an etiological factor in depression (in addition to 5-HT deficiency.”



Therefore, I would now like to explore the kynurenine pathway in depth by not only reviewing information I have presented previously but introducing new, clinically relevant information.  To begin, please take note of Figure 1 highlighting tryptophan metabolism in terms of neurologic function, which comes from the paper “A link between stress and depression: Shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression by Miura et al (5).  As you can see, tryptophan is metabolized through two pathways – the kynurenine pathway and serotonin pathway.  How much goes down each pathway?  As I have indicated previously, the vast majority (well over 90%) normally goes down the kynurenine pathway.  Of course, your first thought may be that this is inherently metabolically destructive since this pathway is linked with, as I have mentioned, both neurodegenerative and mood/behavioral disorders.  The reality, though, is that this pathway has great benefit since it leads to the production of vitamin B3 (niacin) as reflected in the diagram below by “NAD+.”  The pathway is only problematic in terms of neurologic dysfunction when excessive amounts of tryptophan go down this pathway.  This leads to a problem in two ways.  First, excessive tryptophan going down the kynurenine pathway leads to the buildup of neurotoxic metabolites such as quinolinic acid (see Figure 1) which I will discuss in more detail later.  Second, problems occur, particularly in relationship to depression, because when more tryptophan goes down the kynurenine pathway, less goes down the serotonin pathway.  It is interesting that, as Oxenkrug (4) suggested, most researchers, clinicians, and product developers have been independently focusing on optimization of serotonin levels for over 40 years.  However, as I have been suggesting, based on the work of many researchers and clinicians, including one of the developers of the serotonin hypothesis, Gregory Oxenkrug, the best way to deal with the problem is not to independently focus on optimizing serotonin levels but to focus on the cause of the problem, metabolic imbalances that cause increased amounts of tryptophan to go down the kynurenine pathway.



What metabolic imbalances cause too much tryptophan to go down the kynurenine pathway?  There are two.  The first is the primary theme of this series, increased inflammation.  This can be seen in Figure 2, also from the Miura et al paper (5) where the serotonin pathway is indicated by “5-HT” followed by an arrow pointing down and the kynurenine pathway is indicated by “KYN” followed by an arrow pointing up.  As you can see from the figure, increases in inflammatory mediators such as IL-1β, IFN-gamma, and TNF-α will cause increased amounts of tryptophan to go down the kynurenine pathway.  As you will also see, this effect is mediated by the ability of the inflammatory mediators to increase production of an enzyme called indoleamine 2,3 dioxygenase (abbreviated IDO).

As you might also guess, based on much of the research highlighted in this series, the second metabolic imbalance causing too much tryptophan to go down the kynurenine pathway is stress-induced increases in cortisol.  Whereas inflammation increases kynurenine pathway activity by increasing the activity of the enzyme of IDO, cortisol increases kynurenine activity by increasing the activity of the enzyme tryptophan 2,3-dioxygenase (TDO), mainly in the liver.  Oxenkrug (4) states the following about the impact of cortisol on increasing kynurenine pathway activity:

“It is suggested the formation of a ‘vicious circle’ perpetuating the increase of KYN and a decrease of serotonin (5-HT) production in depression due to a) stress hormones -induced activation of tryptophan 2,3-dioxygenase (TDO), the rate-limiting enzyme of the TRY-KYN pathway; b) diminished availability of TRY as an initial substrate of 5-HT biosynthesis due to increased formation of KYN from TRY; and c) increased production of cortisol due to weakening of 5-HT inhibitory effect on amygdaloidal complex.”

Cortisol’s contribution to the increase in tryptophan metabolism down the kynurenine pathway can be seen diagrammatically in Figure 3 which comes from the Oxenkrug paper (4).



Clinical research documenting the relationship between inflammation, increased kynurenine pathway activity and depression

Since much of what was discussed above is based on animal research, do clinical studies exist that document the relationship between inflammation, increased kynurenine pathway activity, and depression?  As you will see from the paper “Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: Role in neuropsychiatric symptoms” by Capuron et al (6), the answer is yes.  In this study of 284 healthy elderly subjects the following was reported:

“As expected, older age was associated with increased concentrations of both IL-6 and neopterin, indicative of immune activation in elderly persons.  In addition, older age together with inflammation correlated negatively with tryptophan concentrations and positively with kynurenine concentrations and with the ratio of Kyn/Trp.  These data are consistent with the hypothesis that immune activation in aging influences the metabolism of amino acids.  In the population under study, decreases in tryptophan concentrations and increases in kynurenine levels and in the ratio of Kyn/Trp were suggestive of increased tryptophan breakdown.  These alterations were associated with immune activation, supporting involvement of IDO in tryptophan degradation.”

Did these findings correlate with depressive symptoms in the study population?  The authors state:

“In conclusion, we found that chronic low-grade inflammation in aging is associated with significant alterations in two enzymatic pathways involved in the metabolism of monoamines.  These alterations, which manifested primarily by increased tryptophan catabolism and altered phenylalanine turnover, might represent major pathophysiological mechanisms in the development of neuropsychiatric symptoms in elderly persons.”

Additional clinical research was discussed in the Miura et al paper (5):

“Some studies have indicated a correlation between the severity of depressive symptoms and serum tryptophan (TRP) decrease and/or KYN increase in depression induced by cytokine therapy.  In the study of women in pregnancy and delivery, depression and anxiety symptoms in the early puerperium are causally related to an increased catabolism of TRP into KYN.  These changes in the plasma TRP and KYN/TRP ratio were significantly related to those in the IL-6 level.

In patients with major depression, the secretion of proinflammatory cytokines from activated macrophages and the synthesis of acute phase proteins from the liver are increased.  In studies evaluating plasma TRP and large neutral amino acids (LNAA) together with indices of immune functions, patients with depression show decreased plasma TRP levels and TRP/LNAA ratios.  Plasma TRP levels negatively correlate to IL-6 production.  Furthermore, depressed subjects have significantly lower serum TRP and albumin levels.  These studies suggest that lower TRP availability to the brain in depression is related to immune responses and lower serum albumin.”


I do realize that the research I have presented thus far seems to suggest a very simplistic point of view that inflammation and stress-induced glucocorticoid aberrations and their correction is all that matters when dealing with patients experiencing neurodegenerative and behavior/mood disorders.  As those of us who have been in practice for several years know, nothing in patient care is ever that simple.  This reality will be demonstrated in the next installment of this series where I discuss clinical research that showed no change in the kynurenine pathway with patients experiencing mood and behavioral disorders.  Will this research lead to the conclusion that virtually everything I have presented relating to the kynurenine pathway is irrelevant clinically?  No!!  Why?  This research, as I will show, will lead us back to where most of us began, an interest in clinical nutrition.  For, what I have omitted so far in this discussion on tryptophan and the kynurenine pathway is a statement of the obvious – tryptophan is a nutrient.  Furthermore, virtually every conversion in the kynurenine pathway requires a nutrient co-factor, primarily vitamin B6.  With this reality in mind, another reality exists suggesting that, with tryptophan or micronutrient deficiency, activity of the kynurenine pathway will not increase with depression and many other mood and behavioral disorders no matter how much inflammation and disturbed cortisol metabolism is present.

Therefore, a primary focus of the next installment will be the discussion of research on the fascinating and sometimes complex interrelationship between nutritional status, the kynurenine pathway, and neurologic dysfunction.

Moss Nutrition Report #270 – 08/01/2016 – PDF Version


  1. Furtado M & Katzman MAExamining the role of neuroinflammation in major depression. Psychiatry Res. 2015;229:27-36.
  2. Rosenblat JD et alInflamed moods: A review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2014;53:23-34.
  3. Lapin IP & Oxenkrug GFIntensification of the central serotonergic processes as a possible determinant of the thymoleptic effect. The Lancet. 1969;1(7586):132-6.
  4. Oxenkrug GFTryptophan-kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: The serotonin hypothesis revisited 40 years later. Isr J Psychiatry Relat Sci. 2010;47(1):56-63.
  5. Miura H, Ozaki N, Sawada M, Isobe K, Ohta T, Nagatsu TA link between stress and depression: Shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression. Stress: The International Journal on the Biology of Stress. 2008;11(3):198-209.
  6. Capuron L, Schroecksnadel S, Féart C, Aubert A, Higueret D, Barberger-Gateau P, et al. Chronic Low-Grade Inflammation in Elderly Persons Is Associated with Altered Tryptophan and Tyrosine Metabolism: Role in Neuropsychiatric Symptoms. Biological Psychiatry. 2011;70(2):175-82.