Beyond depression: the expanding role of inflammation in psychiatric disorders

Abstract

That inflammation plays an important role in depression has garnered considerable attention. Nevertheless, increasing data suggest that inflammation's effects on the brain may have broad relevance to our field, contributing to symptom presentations in many psychiatric disorders beyond depression. The link between inflammation and depression is undeniable1. Patients with major depression reliably exhibit increases in immune molecules that are typically associated with chronic inflammation, including inflammatory cytokines – such as tumor necrosis factor, interleukin (IL)-1 beta and IL-6 – and acute phase proteins, such as C-reactive protein (CRP)2. Increased inflammatory responses also exist in post-mortem brain samples of depressed individuals, with activation of inflammatory signaling pathways in brain parenchyma, trafficking of immune cells to the brain, and activation of microglia2. In addition, administration of inflammatory cytokines such as interferon (IFN)-alpha, or inflammatory stimuli, including typhoid vaccination and endotoxin, induce depressive symptoms. Inflammatory markers, including IL-6 and CRP, predict the development of depressive disorders2. Finally, blockade of inflammatory cytokines has been shown to reduce depressive symptoms, especially in patients with autoimmune and inflammatory disorders3, 4. Although these findings support an impressive argument for a special link between inflammation and depression, increased inflammation only occurs in a subset of depressed patients, being present in 25-50% of them, depending on the sample4, 5. Factors that contribute to increased inflammation in depression include stress, especially early life stress, metabolic factors such as obesity and metabolic syndrome, medical illnesses and their treatments, and treatment resistance2, 6. So, at best, inflamed depressed subjects represent a depressive subtype. Increased inflammation also exists in multiple other psychiatric disorders, including bipolar disorder, anxiety disorders, post-traumatic stress disorder (PTSD) and schizophrenia2, 7. Thus, inflammation is agnostic to diagnosis. Indeed, when significant inflammation is present, its effects on neurotransmitters and neurocircuits contribute to specific symptom profiles that are relevant to multiple psychiatric disorders2. A rich body of data has documented the effects of inflammation on the brain1, 2. Inflammatory cytokines and their downstream signaling pathways reduce monoamine availability, by decreasing the synthesis and release and increasing the reuptake of serotonin, norepinephrine and dopamine. Through effects on astrocytes and microglia, inflammatory cytokines increase the release and decrease the reuptake of glutamate, contributing to a spillover of excess glutamate outside the synapse that can bind to extrasynaptic glutamate receptors, which can lead to excitotoxicity2. Inflammatory cytokines also activate the kynurenine pathway, which generates neuroactive metabolites, including kynurenic acid and quinolinic acid, while also decreasing the production of growth factors, such as brain derived neurotrophic factor, contributing to a disruption of neurogenesis and ultimately synaptic plasticity1, 2. Given that conventional antidepressants act by increasing monoamine availability, have no effects on glutamate metabolism and in part depend on neurogenesis for their efficacy, it is not surprising that inflammation is associated with treatment resistance and predicts response to alternative treatment strategies such as ketamine and electroconvulsive therapy. The effects of inflammation on neurotransmitter systems ultimately affect neurocircuitry. Neuroimaging studies indicate that neurocircuits regulating motivation and motor activity, as well as arousal, anxiety and alarm, are reliably affected2. Administration of inflammatory stimuli – including IFN-alpha, typhoid vaccination and endotoxin – all reduce activity in reward-related regions of the brain, such as the ventral striatum and nucleus accumbens, an effect that is linked to decreased dopamine metabolism as well as increased basal ganglia glutamate, and is accompanied by a decreased willingness to expend effort for reward, while sensitivity to reward remains intact2, 6. Of special relevance to psychiatric patients, endogenous inflammation as reflected by increased CRP is associated with both decreased motivation (a key component of anhedonia) and psychomotor retardation, in association with decreased functional connectivity of the ventral and dorsal striatum with the ventromedial prefrontal cortex8. Although less well established, data indicate that administration of inflammatory stimuli also increases the sensitivity of key brain regions involved in the assessment and response to threat, including the dorsal anterior cingulate cortex, insula, hippocampus and amygdala7. In addition, endogenous increases in inflammation, as reflected by CRP, correlate with decreased functional connectivity betw