ReviewKynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies
Introduction
Mental illness is a pervasive category of disorders that account for a larger proportion of disability in developed countries than any other illness, including cancer and heart disease (Reeves et al., 2011). Depressive disorders are also a global issue and the leading cause of burden and disability worldwide, according to the 2010 Global Burden of Disease of the World Health Organization (Ferrari et al., 2013). Major Depressive Disorder (MDD) is a significant public health issue within the United States that affects roughly 3% of adults, or approximately 9 million people (Reeves et al., 2011). The economic burden of MDD in the United States was estimated to be $210 billion in 2010, an increase in over 20% since 2005 (Greenberg et al., 2015). The burden this places on the patients, health care system, and economy as a whole indicates the importance of efficacious treatment of mental illnesses and continued research into the biological etiologies of these complex conditions (Table 1, Table 2).
The underlying cause of depression has been difficult to elucidate due to the heterogeneous nature of the disease and is based on cluster of symptoms derived from different etiologies. The monoamine deficiency hypothesis has historically been used to explain how depressive symptoms arise from insufficient levels of monoamine neurotransmitters (Delgado, 2006, Schildkraut, 1965). The serotonergic hypothesis was later developed by Van Praag and Korf (1971), followed by the dopaminergic hypothesis of Willner et al. (1990). However, as evidenced by the latent response to antidepressant medications, specifically reuptake inhibitors, and the prevalence of treatment-resistant depression, it is necessary to continue researching alternative treatment methodologies (Trivedi et al., 2008).
Early generations of antidepressants were the monoamine oxidase inhibitors (MOAIs) and the tricyclic antidepressants (TCAs). The mechanism of action of MOAIs is irreversible inhibition of monoamine oxidase, the enzyme responsible for degradation of serotonin, norepinephrine, and dopamine, thereby increasing synaptic concentrations of these neurotransmitters. TCAs act by decreasing reuptake of serotonin and norepinephrine in the presynaptic neurons, effectively increasing their synaptic concentration (DeBattista, 2012). While MAOIs and TCAs do effectively decrease symptoms of depression in a subset of individuals, they are limited by their considerable side effects and are no longer prescribed as first line treatments for depression (Elhwuegi, 2004).
Current first line antidepressant drugs are selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). The selectivity of these drugs has resulted in a treatment option that is better tolerated with fewer side effects, as compared to the MOAIs and TCAs (DeBattista, 2012). However, despite improvements in receptor targeting, SSRIs are no more efficacious than the older TCAs at relieving symptoms of depression (Millan, 2006). Improvements in the side effect profile may increase compliance with treatment programs, but increased efficacy is the ultimate goal for successful pharmacologic management of depression.
Adjuvant therapy with atypical antipsychotics, such as quetiapine, aripiprazole, and olazapine, has been shown to augment the therapeutic effects of SSRIs and has been approved for use in treatment-resistant depression (Bobo and Shelton, 2010, Connolly and Thase, 2011). The detrimental health effects of prolonged atypical antipsychotic use are considered a significant hindrance to the long-term use of this combination, despite the potential benefits. Side effects included significant weight gain, dyslipidemia, and altered glucose metabolism (Davey et al., 2012).
Another important consideration regarding currently available antidepressant treatments is the slow onset of action before clinical improvement is attained. Often, SSRIs and SNRIs require weeks to months of treatment before patients report a diminishment of symptoms (O'Leary et al., 2014). There is also a higher risk of suicide and other deliberate acts of self-harm during the first month of treatment with antidepressants. It has been suggested this is due to an improvement in physical energy that precedes improvements in depressive mood and negative thoughts (Conwell and Heisel, 2012). Identifying faster acting antidepressants is clearly crucial to increasing compliance and decreasing the harmful effects of delayed treatment.
Similarly, related to insufficient therapeutic response of the currently available antidepressants, at least 20% of depressed patients are treatment-resistant—defined as nonresponse to two different pharmacologic classes taken at optimal dose and for sufficient period of time (Berlim and Turecki, 2007). Additionally, approximately 50% of those who are diagnosed with MDD will experience a recurrent or chronic course of the illness (Crown et al., 2002). Major depression is a complex disorder in which gene–environment interactions affects many areas of the body; it stands to reason that manipulating one molecule or neurotransmitter may not effectively cure the disease (Myint, 2012). The insufficient therapeutic effect of the currently available antidepressants has moved the field to focus on alternative mechanisms beyond the monoamine hypothesis. Indeed, over the past two decades there has been a shift from the monoamine hypothesis to pathways involving neuroplasticity impairment. Since patients with autoimmune and inflammatory disorders such as diabetes and fibromyalgia often present with depressive symptoms, it has been proposed that depression may be linked to inflammation (McInnis et al., 2014). Indeed, patients with depression had an increase in serum levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) (O'Brien et al., 2007). Such pro-inflammatory state has been documented in depressed adolescents as well compared to healthy non-depressed adolescents, suggesting that it may play a role early in the course of illness, suggesting that increased inflammation in MDD is not due to chronicity effects (Gabbay et al., 2010b).
The kynurenine pathway (KP) has been hypothesized to play a key role in processes linking peripheral inflammation and CNS alterations by i) reducing tryptophan availability, and ii) production of oxygen radicals and highly potent neurotoxins (Hochstrasser et al., 2011). Thus, tryptophan degradation and its role in the availability of serotonin have brought attention to the kynurenine pathway as a potential target for future research into alternative treatments for depression.
About 99% of tryptophan (TRP) is metabolized by tryptophan 2,3-dioxygenase (TDO) into kynurenine (KYN) in the liver. However, during active inflammation, indoleamine 2,3 –dioxygenase (IDO) is activated in extrahepatic tissues to convert TRP to KYN (Leklem, 1971). Kynurenine by itself in not neuroactive but instead is compartmentally hydroxylated by kynurenine-3-monooxygenase (KMO) into 3-hydroxykynurenine (OHK). Further cleavage of OHK by kynureninase yields 3-hydroxyanthranilic acid (3-HAA). After production of 3-HAA, there are two possible degradation arms: one proceeds with complete oxidation of 3-HAA to form adenosine triphosphate (ATP) and a small quantity of picolinic acid (PIC), while the other pathway produces quinolinic acid (QUIN) which is eventually degraded into nicotinamide adenine dinucleotide (NAD) (Leklem, 1971). Conversely, an alternative pathway is the conversion of KYN to kynurenic acid (KYNA)—a glutamate and 17-nicotinic acetylcholine receptor antagonist—by kynurenine aminotransferases (KATs) (Lopresti et al., 2014). Fig. 1 portrays the tryptophan degradation pathway.
The KYN pathway also plays a role in the metabolism of glucose. The ATP and HAA formed from this pathway activate glycolysis (Quagliariello et al., 1964), through which glycogen is stored in the cells to be utilized in case of stress or glucose need. QUIN has also been shown to inhibit gluconeogenesis (Lardy, 1971). It appears that under normal physiological conditions in the brain, the KYN pathway serves mainly for glycogen storage and the production of small amounts of NAD required for ATP synthesis in the central nervous system (Myint, 2012).
TRP depletion is therefore the result of enhanced tryptophan catabolism by TDO in the liver (Takikawa, 2005) and IDO in the lungs, placenta, blood, and brain (Heyes et al., 1993, Mellor and Munn, 1999). Furthermore, serotonin is degraded by IDO into formyl-5-hydroxykynuramine, in addition to the degradation by monoamine oxidase (Pertz and Back, 1988). The enhanced degradation of tryptophan towards kynurenine and away from production of serotonin has been termed the “kynurenine shunt” (Lapin and Oxenkrug, 1969, Mangoni, 1974).
The tryptophan degradation pathway and the kynurenine shunt have been connected to a number of psychiatric conditions, suggesting that this biochemical process may have far reaching implications. Patients with BD have shown decreased neuroprotective kynurenine metabolites in their hippocampus and amygdala when compared to control patients (Savitz et al., 2015a). Schizophrenic patients were also identified as having an imbalance between the neuroprotective and neurotoxic metabolites of tryptophan degradation (Kegel et al., 2014). MDD is often associated with a systemic pro-inflammatory state that can be tied to increasing levels of IDO activity in the peripheral tissue and the brain (Heyes et al., 1993). This review will present current research that identifies the kynurenine pathway as a prevalent component of the pathophysiology of depression from studies with animal models and human. In addition, this review will highlight studies that focus on treatment targets associated with the kynurenine pathway and antidepressant responses.
Section snippets
Search strategy
For this narrative review, the PubMed/MEDLINE database was searched with the following Boolean terms: “kynurenine”[Mesh] OR “kynureninase”[Supplementary Concept] OR “kynurenine pathway” OR “indolamine-2,3-dioxygenase” OR “tryptophan 2,3-dioxygenase” OR “kynurenic acid” OR “quinolinic acid” OR “anthranilic acid” OR “3 –Hydroxykynurenine” AND “Depression”[Mesh] OR “Depressive Disorder”[Mesh] OR “Depressive Disorder, Major”[Mesh] OR “Depression”; through March 3rd, 2015.
Observational and
Evidence from human studies: central effects
Recent studies have shown that the kynurenine pathway (KP) plays an important role in depression (Fig. 2) (Myint et al., 2007, Myint et al., 2012). Positive correlations were drawn between KYN, QUIN, KYNA and specific pro-inflammatory immunological variables in the cerebrospinal fluid (CSF), and depressive symptoms in patients with hepatitis on IFN-α treatment (Raison et al., 2009). The pro-inflammatory status of patients with major depression has been associated with increases in
Conclusion
Dysregulation in the kynurenine pathway is evident in depression and has been reported by both animal and human studies. In fact, the kynurenine pathway is associated with not only the diagnosis of MDD but also the severity of depressive symptoms. However, the pathophysiologic mechanisms involved in kynurenine pathway dysfunctions are still not fully understood. Results from human studies are not always reproducible and are sometimes contradictory; the findings are dependent on the stage of
Role of funding source
None.
Contributors
GZR, KJ and SET contributed with writing manuscript. AFC contributes to search strategy. GZR and SET did the figures. GZR and KJ prepared the tables. JQ, AFC, VM and GZR contributed with study design and manuscript revision.
Conflict of interest
None.
Acknowledgments
Laboratory of Neurosciences (Brazil) is a center within the National Institute for Molecular Medicine (INCT-MM) and a member of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (JQ, AFC, KJ, and GZR), FAPESC (JQ), Instituto Cérebro e Mente, UNESC (JQ), and LÓréal/UNESCO/ABC Brazil Fellowship for Women in Science 2011 (GZR). JQ, KJ, and AFC are CNPq Research Fellows. Center for Translational Psychiatry (USA) is funded
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