Exploring the association between antidepressants, progression and mortality in Huntington’s disease

Psychiatric symptoms are very common in Huntington's disease (HD). In keeping with other neurodegenerative diseases, there are concerns that antidepressants may worsen disease progression. Previous work on antidepressant effects in HD has been limited by confounding by indication, small sample sizes, short follow-up or a combination of these. We leveraged data from the ENROLL-HD (25550 participants) cohort to determine if 1) symptoms associated with antidepressant initiation are associated with faster disease progression and 2) antidepressants have an impact on disease progression and mortality in people with HD (pwHD) experiencing these symptoms. We first determined the commonest indications for antidepressant prescription in pwHD. We selected adult pwHD (age ≥18, genetically confirmed HD), not on antidepressants and free of antidepressant-indication symptoms at baseline, (N=6166) and used linear mixed models to determine the association between symptoms listed as indications for antidepressant prescription and disease progression and mortality. Using propensity score weighting, we selected adult pwHD who remained antidepressant-naive until an episode of antidepressant-indication symptoms (N=1877) and compared disease progression and mortality between those starting an antidepressant (N=194) before the next follow-up versus those who did not (N=1683). Outcomes were 1) disease progression measured by the composite disease score in ENROLL-HD; and 2) mortality. Depression and anxiety accounted for >80% of indications for antidepressant prescription in pwHD: episodes of depression/anxiety (experienced by 3131/6166) were associated with increased composite disease score progression from 0.46 to 0.52/year (p=3.1x10-11), and increased mortality (Hazard Ratio=1.5,p=9.4x10-6). In pwHD with new depression/anxiety free of antidepressants at symptom onset, antidepressant initiation (N=194/1877) 1) reduced composite disease score decline from 0.89 to 0.53/year (p=0.002); and 2) reduced all cause mortality(Hazard Ratio 0.38,p=0.04). An exploratory analysis of antidepressant classes showed that TCAs reduced suicide and non-suicide mortality; SSRIs and atypical agents reduced suicide risk, whilst SNRIs reduced non-suicide related mortality. Depression and anxiety are associated with more rapid disease progression and increased mortality in HD. In pwHD affected by depression and anxiety, antidepressant initiation slows disease progression and reduces mortality risk, with preliminary evidence of antidepressant-class specific reduction in both suicide and non-suicide mortality risk. This finding warrants further investigation in both HD and other neurodegenerative diseases.