Inflammatory Depression-Mechanisms and Non-Pharmacological Interventions

Abstract

Treatment of depression is hampered by the failure to identify distinct symptom profiles with distinct pathophysiologies that differentially respond to distinct treatments. We posit that inflammatory depression is a meaningful depression subtype associated with specific symptoms and biological abnormalities. We review several upstream, potentially causative, mechanisms driving low-grade inflammation in this subtype of depression. We also discuss downstream mechanisms mediating the link between inflammation and symptoms of depression, including alterations in dopaminergic neurotransmission and tryptophan metabolism. Finally, we review evidence for several non-pharmacological interventions for inflammatory depression, including probiotics, omega-3 fatty acids, and physical exercise interventions. While some evidence suggests that these interventions may be efficacious in inflammatory depression, future clinical trials should consider enriching patient populations for inflammatory markers, or stratify patients by inflammatory status, to confirm or refute this hypothesis.

Keywords: depression; dysbiosis; exercise; inflammation; n-3 PUFAs.

Figure 1

Hypothetical model of bidirectional interactions between systemic low-grade inflammation and depression. From bottom left: Negative health behaviors such as poor dietary habits, stress, and a sedentary lifestyle could trigger and/or enhance inflammatory responses. Below, we discuss two potential mechanisms mediating the effects of such behaviors on inflammation; increased dietary n-6/n-3 ratio and dysbiosis. Subsequent pro-inflammatory signaling may trigger oxidative stress and lead to alterations in dopamine release, reuptake and synthesis. This in turn may generate symptoms of psychomotor retardation and motivational anhedonia, further reinforcing a state of sickness behavior, and may induce, enhance, or maintain depression and more negative health behaviors. Abbreviations: omega-6 (n-6), omega-3 (n-3), arachidonic acid (AA), lipopolysaccharide (LPS), mitogen-activated protein kinases (MAPK).

Figure 2

Dysbiosis and increased gut permeability may lead to translocation of LPS from the gut lumen into the circulation triggering low-grade inflammation. SCFAs also translocate into circulation and may have several beneficial effects including enhancing the integrity of the intestinal barrier and the BBB. Circulating pro-inflammatory cytokines either signal to the brain via the vagal nerve or cross the BBB and thereby contribute to neuroinflammation and microglia activation. Abbreviations: lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), lipopolysaccharide-binding protein (LBP), blood-brain barrier (BBB).

Figure 3

Enzymes LOX and COX are involved in various steps of PUFA metabolization, affecting the pro/anti-inflammatory balance. Abbreviations: omega-6 (n-6), omega-3 (n-3), polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), phospholipidase 2 (PLA2), arachidonic acid (AA), lipoxygenase (LOX), cyclooxygenase (COX), prostaglandines (PG), thromboxanes (TX), leukotrienes (LT).

Figure 4

Metabolization of the essential amino acid tryptophan is shown in a simplified schematic with focus on the metabolites discussed in this review. Marked in red is the activation of IDO by pro-inflammatory cytokines, triggering the formation of kynurenine from tryptophan. This is the first and rate-limiting step of the kynurenine pathway. Abbreviations: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO), 3-hydroxykynurenine (3-HK), kynurenic Acid (Kyn-a).

Figure 5

Crosstalk between the immune and dopaminergic systems. A pro-inflammatory state is triggered by cytokines produced by microglia or entering the central nervous system (CNS) from the peripheral circulation (a). Cytokine-actions with increased oxidative stress through formation of ROS may reduce part of the BH4 pool, resulting in less availability of BH4 for dopamine synthesis (b). BH4 availability is further reduced when cytokines activate NOS, demanding BH4 as co-factor in production of NO, further adding to oxidative stress (c). To the right in the figure, the “neurotoxic” and cytokine-induced branch of kynurenine pathway is presented, which occurs in microglia (d). The KP-metabolite quinolinic acid has neurotoxic properties and adds to oxidative stress. Lastly, available dopamine in pre-synaptic clefts is further reduced as cytokines both decrease VMAT2’s packaging of dopamine into vesicles for release, and increase DAT expression and function for re-uptake (e) [67]. Abbreviations: nitric oxide synthase (NOS), nitric oxide (NO), reactive oxygen species (ROS), tetrahydrobiopterin (BH4), indoleamine 2,3-dioxygenase (IDO), vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT).