Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

Abstract

Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitaryadrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamopituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.

The comorbidity of epilepsy and depression: diagnosis and treatment

“…In 2012, Pineda et al [72] treated Wistar rats with comorbid epilepsy and depression with selective serotonin reuptake inhibitors (SSRIs) and IL-1 receptor antagonists (IL-1Ra); the results showed that fluoxetine monotherapy was ineffective and IL-1Ra reversed anhedonia and partially improved other depressive disorders. The combination of the two drugs eliminated all the symbolic characteristics of depression in epilepsy and improved the HPA axis.…”

Lamotrigine positively affects the development of psychiatric comorbidity in epileptic animals, while psychiatric comorbidity aggravates seizures

“…Both clinical and animal studies have been performed in this field in order to define or find a correlation between these pathologies [4,[14][15][16][17]. Good results have also been achieved in identifying some neurobiological common basis and pharmacological correlates [18][19][20][21][22][23]. Although behavior has been experimentally studied in several models of epilepsy, only few can be regarded as animal models of epilepsy and comorbid mood disorder, namely, the genetically epilepsy-prone rats (GEPRs) [24] and some genetic models of absence epilepsy (i.e., GAERS and WAG/Rij rats) [25].…”

Biomarkers of Epileptogenesis: Psychiatric Comorbidities (?)

“…Thus, it is conceivable that the disruption of IL-1β signaling in the epileptic brain and subsequent normalization of 5-HT 1A autoreceptor function would restore the effectiveness of SSRI. This suggestion has been confirmed directly, whereby adjunctive therapy with a low, ineffective on its own, dose of IL-1RA renders fluoxetine therapeutically effective in animals with epilepsy-associated depression [193].…”