Different depression: motivational anhedonia governs antidepressant efficacy in Huntington’s disease
Authors: McLauchlan Duncan James , Lancaster Thomas , Craufurd David , Linden David E J , Rosser Anne E 
Published: November 2022

Abstract
Depression is more common in neurodegenerative diseases such as Huntington’s disease than the general population. Antidepressant efficacy is well-established for depression within the general population: a recent meta-analysis showed serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants and mirtazapine outperformed other antidepressants. Despite the severe morbidity, antidepressant choice in Huntington’s disease is based on Class IV evidence. We used complementary approaches to determine treatment choice for depression in Huntington’s disease: propensity score analyses of antidepressant treatment outcome using the ENROLL-HD data set, and a dissection of the cognitive mechanisms underlying depression in Huntington’s disease using a cognitive battery based on the Research Domain Criteria for Depression. Study 1 included ENROLL-HD 5486 gene-positive adult patients started on an antidepressant medication for depression. Our outcome measures were depression (Hospital Anxiety and Depression Scale or Problem Behaviours Assessment ‘Depressed Mood’ item) at first follow-up (primary outcome) and all follow-ups (secondary outcome). The intervention was antidepressant class. We used Svyglm&Twang in R to perform propensity scoring, using known variables (disease progression, medical comorbidity, psychiatric morbidity, sedatives, number of antidepressants, demographics and antidepressant contraindications) to determine the probability of receiving different antidepressants (propensity score) and then included the propensity score in a model of treatment efficacy. Study 2 recruited 51 gene-positive adult patients and 26 controls from the South Wales Huntington’s Disease Management Service. Participants completed a motor assessment, in addition to measures of depression and apathy, followed by tasks measuring consummatory anhedonia, motivational anhedonia, learning from reward and punishment and reaction to negative outcome. We used generalised linear models to determine the association between task performance and depression scores. Study 1 showed selective serotonin reuptake inhibitors outperformed serotonin norepinephrine reuptake inhibitors on the primary outcome (P = 0.048), whilst both selective serotonin reuptake inhibitors (P = 0.00069) and bupropion (P = 0.0045) were superior to serotonin norepinephrine reuptake inhibitors on the secondary outcome. Study 2 demonstrated an association between depression score and effort for reward that was not explained by apathy. No other mechanisms were associated with depression score. We found that selective serotonin reuptake inhibitors and bupropion outperform serotonin norepinephrine reuptake inhibitors at alleviating depression in Huntington’s disease. Moreover, motivational anhedonia appears the most significant mechanism underlying depression in Huntington’s disease. Bupropion is improves motivational anhedonia and has a synergistic effect with selective serotonin reuptake inhibitors. This work provides the first large-scale, objective evidence to determine treatment choice for depression in Huntington’s disease, and provides a model for determining antidepressant efficacy in other neurodegenerative diseases.