Neuropsychiatric adverse reactions in patients treated with denosumab: two case reports and a review of data from the FDA Adverse Event Reporting System (FAERS).

Denosumab is a human monoclonal antibody indicated for patients with osteoporosis and a high risk of fractures. It targets RANKL, the receptor activator of NF-κB (RANK) ligand, blocking RANKL-RANK interaction and leading to rapid osteoclast-mediated bone resorption inhibition. But RANK is widely expressed in neurons, microglia, and astrocytes. RANKL/RANK/NF-κB system can play an important role in the neuroinflammatory response, depressive behavior, memory impairments, and neurotrophism. We present two well-documented case reports of recurrent neuropsychiatric manifestations in patients treated with denosumab and a descriptive review of similar cases reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database between 2012 and 2022. Only those reported by healthcare professionals, coding denosumab as the only suspected drug, were retained. An 81-year-old woman with pre-existing mild cognitive impairment suffered two acute confusional episodes and another 81-year-old woman with depression in remission suffered two depressive recurrences with anxiety and psychomotor inhibition, in both cases following sequential administrations of denosumab without underlying calcium/phosphate imbalance. Scores on Naranjo Adverse Drug Reaction Probability Scale were 6 and 7, respectively, suggesting a probable causal relationship. Of the 91,151 cases with denosumab exposure reported to FAERS, 5.7% were related to psychiatric/neurological disorders and 23.8% of these corresponded to cognitive impairment, depressive/mood disturbances, or psychomotor retardation. Denosumab may cause transient but severe neuropsychiatric symptoms by several mechanisms involving RANKL blockade and subsequent immuno-inflammatory changes, at least in subjects with pre-existing neurobiological vulnerability. We recommend caution and careful monitoring of these patients following denosumab administrations.

Association study of polymorphisms within inflammatory genes and methylation status in treatment response in major depression.

BACKGROUND: Although pharmacogenetics for major depressive disorder (MDD) is gaining momentum, the role of genetics in differences in response to antidepressant treatment is controversial, as they depend on multifactorial and polygenic phenotypes. Previous studies focused on the genes of the serotonergic system, leaving apart other pathological factors such as the inflammatory pathway. The main objective of the study was to assess whether treatment response might be associated with specific inflammation-related genetic variants or their methylation status. METHODS: 41 SNPs in 8 inflammatory genes: interleukin (IL) 1-ß, IL2, IL6, IL6R, IL10, IL18, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were genotyped in 153 patients with MDD, who were evaluated with the Mausdley Staging Method to determine treatment response profiles. Pyrosequencing reactions and methylation quantification were performed in a PyroMark Q24 in 5 selected CpG islands of IL1- ß, IL6 and IL6R. Linear and logistic regression analyses were conducted, including age and gender as covariates using PLINK 1.07. RESULTS: Allelic distribution of IL1- ß rs1143643 was significantly associated with MSM scores (FDR corrected p = 0.04). Allelic distribution of IL6R rs57569414 showed a trend towards significance with MSM scores (p = 0.002; FDR corrected p = 0.07). Haplotype analyses showed associations between allelic combinations of IL1-ß and IL10 with treatment response (FDR corrected p < 0.01). Methylation percentage of treatment responders was only higher in an IL6R CpG island (p < 0.05). CONCLUSIONS: These exploratory findings suggest that IL1-ß and, marginally, IL6R polymorphisms may affect treatment response in major depression. If confirmed, these results may account for the heterogeneous phenotypes of major depression that underlie differences in treatment response.

Cognitive functioning after deep brain stimulation in subcallosal cingulate gyrus for treatment-resistant depression: an exploratory study.

Deep brain stimulation (DBS) is being investigated as a therapeutic alternative for patients with treatment-resistant depression (TRD), but its cognitive safety has been scarcely explored. The aim of this exploratory study is to evaluate cognitive function of patients before and after deep brain stimulation of the subgenual cingulate gyrus (SCG). Eight treatment-resistant depressed patients were implanted in subgenual cingulate gyrus. A neuropsychological battery was used to evaluate patients before surgery and 1-year after. A matched group of eight first-episode patients was also assessed. A MANOVA was performed for each cognitive domain and those tests showing main time effects were then correlated with depressive symptoms and with medication load. There were significant group and time effects for memory and a group effect for language. No significant interactions between groups or cognitive domains were observed. Medication load was negatively correlated with memory at time 1, and clinical change negatively correlated with memory improvement. These findings support the cognitive safety of DBS of subgenual cingulate gyrus, as cognitive function did not worsen after chronic stimulation and memory performance even improved. The results, though, should be interpreted cautiously given the small sample size and the fact that some treatment-resistant patients received electroconvulsive therapy (ECT) before implantation.

Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression.

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-µs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.