Anti-cytokine agents for anhedonia: targeting inflammation and the immune system to treat dimensional disturbances in depression

Abstract

The etiology of mood disorders is mechanistically heterogeneous, underscoring the need for a dimensional approach to identify and develop targeted treatments in psychiatry. Accumulating evidence implicates inflammation as an important contributor to the pathophysiology of depression and presents the immune system as a viable therapeutic target that may be more proximate to the pathogenic nexus of brain-based disorders in specific subpopulations. Anhedonia is a transdiagnostic (e.g. Parkinson's disease, diabetes mellitus, rheumatic diseases), yet specific, and clinically relevant symptom dimension subserved by well-characterized neurobiological and neurophysiological substrates of the positive valence systems (PVS). Brain circuits, nodes, and networks, as well as cellular and molecular pathways (e.g. dopaminergic transmission; excitotoxicity; synaptic plasticity), subserving anhedonia are preferentially affected by inflammatory processes. To our knowledge, no published randomized, controlled clinical trial in populations with mood disorders has, to date, primarily sought to determine the effects of an anti-inflammatory agent on PVS functions or pathophysiology. Three ongoing clinical trials aim to investigate the effects of anti-TNF-alpha biologic infliximab on measures of anhedonia [ClinicalTrials. gov identifier: NCT02363738], motivational behavior and circuitry [ClinicalTrials.gov identifier: NCT03006393], and glutamatergic changes in the basal ganglia [ClinicalTrials.gov identifier: NCT03004443] in clinical populations with unipolar or bipolar depression. Positive results would further instantiate the relevance of inflammatory processes and the immune system in the pathophysiology of mood disorders and provide the impetus to develop scalable treatments targeting inflammation and the immune system to mitigate transdiagnostic, dimensional disturbances in brain-based disorders.

Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression

“…Our findings could have implications for anti-inflammatory treatment 6 , 65 and preventative care 66 – 69 in a subgroup of depressed patients with sickness-behavior-related symptoms 70 . Research is underway to investigate the effects of anti-TNF-alpha biologic infliximab on measures of anhedonia, motivational behavior, and glutamatergic changes in the basal ganglia 71 and to investigate the effects of simvastatin for treatment-resistant MDD 72 and patients with comorbid obesity and MMD 73 . We recommend that future studies approach depression as a group of separate symptoms rather than as a unified construct.…”

Depression and the risk of rheumatoid arthritis

“…JAK/STAT modulation is also of theoretical benefit, as this pathway is involved in neurogenesis, synaptic plasticity, gliogenesis and microglial activation, and also with some antidepressants having a mechanism of action mediated by JAK/STAT-dependent mechanisms [5 ▪ ]. Other randomized trials are in progress looking at the effects of anti-TNFα therapy in anhedonia [37].…”

Cytokine storm induced new onset depression in patients with COVID-19. A new look into the association between depression and cytokines -two case reports

“…Contemporary literature suggests that new onset depression may be caused by inflammation initiated during the active phase of the COVID-19 infection which results in a cytokine surge ( 7 ). Over the past 2 decades, an increasing amount of literature supports the hypothesis that inflammation contributes to new onset depression ( 8 ). In addition, this hypothesis suggests that the immune system and its response plays a significant role in the pathophysiology of mood disorders.…”