Genetic risk for chronic pain is associated with lower antidepressant effectiveness: Converging evidence for a depression subtype

Abstract

Introduction: Chronic pain and depression are highly comorbid and difficult-to-treat disorders. We previously showed this comorbidity is associated with higher depression severity, lower antidepressant treatment effectiveness and poorer prognosis in the Australian Genetics of Depression Study. Objective: The current study aimed to assess whether a genetic liability to chronic pain is associated with antidepressant effectiveness over and above the effect of genetic factors for depression in a sample of 12,863 Australian Genetics of Depression Study participants. Methods: Polygenic risk scores were calculated using summary statistics from genome-wide association studies of multisite chronic pain and major depression. Cumulative linked regressions were employed to assess the association between polygenic risk scores and antidepressant treatment effectiveness across 10 different medications. Results: Mixed-effects logistic regressions showed that individual genetic propensity for chronic pain, but not major depression, was significantly associated with patient-reported chronic pain (PainPRS OR = 1.17 [1.12, 1.22]; MDPRS OR = 1.01 [0.98, 1.06]). Significant associations were also found between lower antidepressant effectiveness and genetic risk for chronic pain or for major depression. However, a fully adjusted model showed the effect of PainPRS (adjOR = 0.93 [0.90, 0.96]) was independent of MDPRS (adjOR = 0.96 [0.93, 0.99]). Sensitivity analyses were performed to assess the robustness of these results. After adjusting for depression severity measures (i.e. age of onset; number of depressive episodes; interval between age at study participation and at depression onset), the associations between PainPRS and patient-reported chronic pain with lower antidepressant effectiveness remained significant (0.95 [0.92, 0.98] and 0.84 [0.78, 0.90], respectively). Conclusion: These results suggest genetic risk for chronic pain accounted for poorer antidepressant effectiveness, independent of the genetic risk for major depression. Our results, along with independent converging evidence from other studies, point towards a difficult-to-treat depression subtype characterised by comorbid chronic pain. This finding warrants further investigation into the implications for biologically based nosology frameworks in pain medicine and psychiatry.

A shared genetic signature for common chronic pain conditions and its impact on biopsychosocial traits

“…For instance, statins and beta-blockers may serve as proxies for cardiovascular disease, while antidepressants may reflect the relationship between chronic pain and depression, 12 or conversely, the use of antidepressants to treat chronic pain conditions. 24,25 Our findings indicate that while pain conditions and psychological traits (e.g., depression) are frequently co-morbid at a phenotypic level, the pattern of causal relationships between them are heterogenous across the various chronic pain types. For instance, we observed genetic evidence of causal relationships across both directions between depression-associated traits and chronic headaches & back pain (i.e., a proportion of relationships are pain → depression and others are depression → pain [Supplementary Tables S2, S8]).…”

“…Traits implicated in our findings may represent candidates for patient classification, risk stratification and pain phenotyping in clinical management of chronic pain conditions. 21 Further, the proposition of a shared genetic signature underlying different types of regional chronic pain invites further investigation of genetic risk for chronic pain, 22,23 which may have potential applications for genetic stratification of patients in clinical trials, 24 to allow targeting of patients most at risk of developing chronic pain. Based on the precedent for genetically supported therapeutic targets, 2,3 traits with genetic causal effects identified in our study may represent potential treatment targets in management of chronic pain, providing convergent support for established approaches for treatment (e.g., weight-loss in knee osteoarthritis 25 ) or prevention of chronic pain (e.g., targeting post-traumatic stress after injury 26,27 ), as well as insight for development of emerging strategies (e.g., dietary 28 ).…”

“…For instance, statins and beta-blockers may serve as proxies for cardiovascular disease, while antidepressants may reflect the relationship between chronic pain and depression, 12 or conversely, the use of antidepressants to treat chronic pain conditions. 24,25…”

“…Traits implicated in our findings may represent candidates for patient classification, risk stratification and pain phenotyping in clinical management of chronic pain conditions. 21 Further, the proposition of a shared genetic signature underlying different types of regional chronic pain invites further investigation of genetic risk for chronic pain, 22,23 which may have potential applications for genetic stratification of patients in clinical trials, 24 to allow targeting of patients most at risk of developing chronic pain.…”

“…Further work is required such as: (i) genetic epidemiology studies collecting data on more specific chronic pain diagnoses, clinical traits (e.g., pro-& anti-nociceptive phenotypes, medication/treatment responses 24 ) and epigenetic factors (e.g., early life stress, physical activity);…”