{"source": "PMC13099390", "title": "Delay discounting correlates with depression but does not predict relapse after antidepressant discontinuation", "text": "# Delay discounting correlates with depression but does not predict relapse after antidepressant discontinuation\n\n## Abstract\nApproximately one third of people with Major Depressive Disorder (MDD) experience a relapse within six months of discontinuing antidepressant medication (ADM), however, reliable predictors of relapse following ADM discontinuation are currently lacking. A putative behavioural predictor is delay discounting, which measures a person’s impatience to receive reward. Previous studies have linked delay discounting to both MDD and reduced serotonergic function, rendering it a plausible candidate predictor. In this multi-site study we measured delay discounting in participants with remitted MDD (N = 97), before and within six months after discontinuation of ADM, and in matched controls without a lifetime history of MDD (N = 54). Using predictive models, we tested whether either baseline discounting, or an early change in discounting following ADM discontinuation, predicted depressive relapse over a six month follow up period. We also tested differences between remitted MDD and control groups in delay discounting at baseline, and associations between discounting and depressive symptoms. We found that the remitted MDD group, compared to the control group, showed significantly higher (p < 0.05; Cohen’s d = 0.34) discounting at baseline. In addition, baseline discounting was positively correlated with depression rating scores (Spearman ρ = 0.24). However, delay discounting did not increase following ADM discontinuation. Neither baseline discounting, nor a change in discounting following ADM discontinuation, predicted subsequent depressive relapse. We conclude that delay discounting is elevated in remitted MDD treated with antidepressant medication. However, delay discounting neither increases following ADM discontinuation, nor does it prospectively predict depressive relapse. These results suggest that delay discounting in Major Depressive Disorder has little relationship with illness trajectory following ADM discontinuation.\n\n## Full Text\n\n\n### Introduction\nDepressive disorders are estimated to be among the largest contributors to years lived with disability worldwide [1, 2]. This huge burden of morbidity is largely attributable to the chronic or recurring pattern [3, 4] that often characterizes depression. Furthermore, although many people derive benefit from antidepressant medication, approximately one in three will experience another depressive episode within six months of antidepressant discontinuation [5]. An initially successful treatment is therefore still too often followed by a relapse.\nRandomized controlled trials indicate that continual maintenance treatment with antidepressant medication reduces the risk of relapse or recurrence [5–8]. Nevertheless, maintenance treatment does not completely eliminate the risk of suffering from breakthrough depression while still on treatment, or from further depressive episodes after subsequent discontinuation [9]. Additionally, many people experience unpleasant side effects of antidepressant medication, such as weight gain and sexual dysfunction [10]. Thus, not all individuals who experience a depressive episode benefit equally from continuing medication after achieving remission. There is therefore a pressing clinical need to distinguish those who can safely discontinue antidepressants from those with a higher risk of relapse following discontinuation.\nCurrent clinical guidelines recommend continued treatment for at least six months after obtaining remission from a first episode of depression, and at least two years of treatment after remission for patients deemed to be at high risk of relapse [11, 12]. The risk of relapse is assessed using one or more of different predictors, such as the number of prior episodes [11], physical and psychological comorbidities [11], ethnicity [13], a melancholic subtype [14], anxiety [15], somatic pain [16], and previous response to medication [17]. However, several of these predictors lack robust replication studies to support their relevance (for a review see [18]). Where replications do exist, these sometimes reach conflicting conclusions, for example regarding the effect of the number of previous episodes on future relapse risk [6, 19]. Other predictors are difficult to reliably measure; for example, in clinical practice, previous response to treatment is often unclear [18]. This uncertainty not only calls for continued investigation into existing markers of relapse, but also motivates a search for novel relapse predictors.\nIn this study we evaluate delay discounting, which is thought to quantify a person’s impatience to receive reward, as a candidate behavioural predictor of depressive relapse following antidepressant discontinuation1. Delay discounting can be quickly assessed, by offering participants a series of choices between immediate and delayed rewards of varying magnitude. Conventionally, such choices are used to estimate a parameter termed the ‘discount rate’, which captures how steeply the subjective value of reward decreases as it is delayed. Higher discount rates imply a steeper decrease in reward value with delay, and thereby greater impatience. The behavioral and neural correlates of delay discounting have been extensively studied (see e.g. [20–23]).\nExisting evidence suggests that delay discounting is a plausible candidate marker of depressive relapse following antidepressant discontinuation. Firstly, studies have reported higher delay discount rates amongst people with Major Depressive Disorder (MDD) when compared to healthy controls [24–27]. Notably differences in discounting between depressed participants and non-depressed controls are not found reliably across all studies and comparisons. Some studies find no significant difference [28, 29], while others find differences from healthy controls only amongst sub-groups of depressed participants [24, 27], or only for larger rewards [26]. Nevertheless, a meta-analysis of seven case-control studies supports a conclusion of elevated discounting in MDD, with a small effect size (Hedges g = 0.38) [30]. The greater impatience observed in MDD has been interpreted as resulting from the pessimistic future outlook which is a feature of depression [4, 31–36] and as reflecting the loss of evaluative differentiation concerning future outcomes [37].\nSecondly, most antidepressant medications are believed to increase serotonin levels, which is thought to be crucial for their therapeutic effect [38, 39], while discounting is also found to be sensitive to serotonergic manipulations. Tryptophan depletion, which lowers brain serotonin levels, induces acute symptomatic relapse in patients with remitted depression [40, 41], and has been found to increase discount rates in healthy participants [42, 43] (though Tanaka et al. did not replicate this effect) [44]. Furthermore, a small study found that discount rates were reduced by acute administration of a selective serotonin reuptake inhibitor amongst participants with Attention Deficit Hyperactivity Disorder [45]. More definitively, rodent studies have demonstrated that stimulating serotonergic neurons in the dorsal raphe, or their projections to medial prefrontal cortex, augments an animal’s willingness to wait for reward [46, 47], while lesioning or blocking serotonergic neurotransmission increases impatience [48–50].\nIn summary, evidence indicates that discounting is increased in MDD, increases following serotonin depletion and decreases following enhancement of serotonin release. Thus, delay discounting is a candidate marker of both serotonergic function and depressive cognition. Based on these findings, our primary hypothesis was that patients with remitted MDD who show higher delay discounting are at increased risk of relapse following antidepressant discontinuation. A secondary hypothesis was that antidepressant discontinuation results in an increase in delay discounting, and that the magnitude of this early increase in discounting predicts subsequent depressive relapse. We tested these hypotheses within the AIDA (Antidepressiva Absetzstudie) study – a two-center, longitudinal, observational study of antidepressant discontinuation [51–53]. We also tested how delay discounting is related to depression symptom scores and other psychometric data amongst this sample of patients with remitted depression.\n\n\n### Methods and materials\nData from the AIDA study has been analysed previously [51–53]. However, the delay discounting data reported here have not previously been examined. The dataset consists of: i) participants treated with antidepressant medication (ADM), who decided to discontinue their antidepressant medication independently from study participation, after being diagnosed with Major Depressive Disorder, and ii) healthy control (HC) participants matched for age, sex and education to the ADM group. Healthy controls were excluded if there was a lifetime history of DSM IV Axis I or Axis II disorders, with the sole exception of nicotine dependence. Recruitment criteria for the ADM group included: (a) at least one severe [54] or multiple depressive episodes, (b) initiation of antidepressant treatment during the last depressive episode, and (c) achieving stable remission, assessed by a score of less than 7 on the Hamilton Depression Rating Scale 17 [55] for 30 days. See [51–53] for detailed inclusion and exclusion criteria.\nAll participants gave informed written consent and received monetary compensation for their time. Ethical approval for the study was obtained from the cantonal ethics commission Zurich (BASEC: PB_2016-0.01032; KEK-ZH: 2014-0355) and the ethics commission at the Campus Charité-Mitte (EA 1/142/14), and procedures were carried out in accordance with the Declaration of Helsinki.\nAs shown in Fig. 1, participants were assessed and compared at Main Assessment 1 (MA1) to identify features characterising the remitted, medicated state. Next, patients were randomised to either discontinue their medication at MA1 (MA1-D-MA2) or enter a waiting period approximately matched to the length of discontinuation time (group MA1-MA2-D). Patients in the waiting group discontinued their ADM after Main Assessment 2 (MA2). Details of the randomisation procedure are provided in the Supporting Material. After discontinuation, all patients entered a six month follow-up (FU) period, wherein some patients experienced a relapse.Fig. 1Study Design.We recruited remitted patients treated with antidepressant medication (ADM) and healthy controls matched for age, sex and education to the patients group. Patients were assessed at Main Assessment 1 (MA1) to identify features characterizing the remitted, medicated state. Next, patients were randomized to either discontinue their medication before MA2 (bottom arm, “group MA-1-D-MA2” or enter a waiting period while continuing their ADM, matched to the length of discontinuation time (top arm, “group MA1-MA2-D”). Discounting was assessed at MA1 and MA2, to investigate the effects of discontinuation. Patients in the MA1-MA2-D discontinued their ADM after MA2. After discontinuation, all patients entered the follow-up (FU) period of 6 months, during which some patients relapsed. Numbers below each box indicate the number of subjects in that group. The numbers below each box indicate the number of subjects in the corresponding group.\nWe recruited remitted patients treated with antidepressant medication (ADM) and healthy controls matched for age, sex and education to the patients group. Patients were assessed at Main Assessment 1 (MA1) to identify features characterizing the remitted, medicated state. Next, patients were randomized to either discontinue their medication before MA2 (bottom arm, “group MA-1-D-MA2” or enter a waiting period while continuing their ADM, matched to the length of discontinuation time (top arm, “group MA1-MA2-D”). Discounting was assessed at MA1 and MA2, to investigate the effects of discontinuation. Patients in the MA1-MA2-D discontinued their ADM after MA2. After discontinuation, all patients entered the follow-up (FU) period of 6 months, during which some patients relapsed. Numbers below each box indicate the number of subjects in that group. The numbers below each box indicate the number of subjects in the corresponding group.\nThe data analysis plan for the current study was preregistered [56], and is provided in Supplementary Table 1. All participants answered rating questionnaires, among which, the measures of prior interest for the present study were Hamilton Depression Scale (HAM-D), Emotion Regulation Questionnaire (ERQ), Brief Self-Control Scale (BSCS), Daily Hassles, Satisfaction with Life Scale (SWLS), Adverse Childhood Experience (ACE), Childhood Trauma Questionnaire (CTQ), Traumatic Life Events Questionnaire (TLEQ), and the Mehrfachwahl-Wortschatz-Intelligenztest (MWT-B).\nWe also conducted a power analysis for group differences prior to the study commencement. The description of which is provided in the Supporting Material.\nDelay-discounting procedures estimate the indifference point at which a smaller but immediately available reward, r, and a larger but delayed reward, R, have approximately the same subjective value to the participant. Here, participants completed two delay discounting tasks to estimate indifference points for rewards across a range of delays. The first task was Kirby’s monetary choice questionnaire (MCQ) [57], which consists of 27 items each asking participants to choose between an immediate and a delayed reward. In the second task, participants answered an adaptive version of the questionnaire [58], wherein a discount rate is estimated after each choice the subject makes, and the next immediate and delayed rewards offered are provided from the currently estimated indifference point. At each step, this procedure elicits the most informative choice, based on a participant’s estimated discount rate. The procedure continues until a stable estimation of the indifference point is reached [58]. Including two tasks, rather than one, was intended to bolster reliability.\nIn this study, rewards were hypothetical. Although one previous study found a small reduction in discount rates for real as opposed to hypothetical rewards [59], a number of other studies report no systematic differences in discounting for real and hypothetical rewards [60–62], suggesting that assessing discounting for hypothetical rewards is a valid procedure.\nWe modeled the participants’ choices using a standard hyperbolic model [63]:1\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$V\\left(R,d\\right)=\\frac{R}{1+{Kd}}.$$\\end{document}VR,d=R1+Kd.\nThis equation describes the subjective value, V, of a reward, R, available after a delay d. \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K \\,{{{\\rm{is}}}}\\; {{{\\rm{a}}}}\\; {{{\\rm{discount}}}}\\; {{{\\rm{rate}}}},{{{\\rm{estimated}}}}\\; {{{\\rm{from}}}}\\; {{{\\rm{participants}}}}{{\\hbox{'}}}{{{\\rm{indifference}}}}\\; {{{\\rm{points}}}}.\\;{{{\\rm{Higher}}}}\\; {{{\\rm{values}}}}\\; {{{\\rm{of}}}}$$\\end{document}Kisadiscountrate,estimatedfromparticipants’indifferencepoints.Highervaluesof\nK reflect greater impatience and reduced tolerance for delay [52]. The hyperbolic model of delay discounting is illustrated in Fig. 2. A generalization of this hyperbolic model includes an exponent on the delay term, which adjusts the curvature of the discount curve [64, 65]. Here, since we are interested in individual differences, we omit this exponent in favour of the standard hyperbola, which captures variability in discounting with a single parameter, K.Fig. 2Hyperbolic delay discounting.Illustration of the hyperbolic model of delay discounting for a subset of nine questions from Kirby’s monetary choice questionnaire (MCQ) consisting of small amount of delayed reward (25$–35$). Each open white circle represents one of the nine questions: its X-coordinate indicates how long one would have to wait for the delayed reward (delay, d), while its Y-coordinate indicates the value of the immediate, no delay reward relative to the delayed reward (relative value, V/R). Each dotted curve represents the hyperbolic delay discount rate, K, at which a participant would be indifferent between immediate and delayed rewards for each specific choice. The dashed curve corresponds to a discount function with K = 0.01. A person with this fitted value of the discount rate would choose the immediate rewards in the questions with \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K$$\\end{document}K values larger than \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0.01$$\\end{document}0.01 (bottom four hyperbolic curves), and would choose the delayed reward on the questions with \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K$$\\end{document}K values smaller than \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0.01$$\\end{document}0.01 (top five hyperbolic curves). Open grey circles represent the subjective values, V(R, d), predicted by the dashed curve for each value of delay (d) of the nine questions. Adapted from [49, 59, 71].\nIllustration of the hyperbolic model of delay discounting for a subset of nine questions from Kirby’s monetary choice questionnaire (MCQ) consisting of small amount of delayed reward (25$–35$). Each open white circle represents one of the nine questions: its X-coordinate indicates how long one would have to wait for the delayed reward (delay, d), while its Y-coordinate indicates the value of the immediate, no delay reward relative to the delayed reward (relative value, V/R). Each dotted curve represents the hyperbolic delay discount rate, K, at which a participant would be indifferent between immediate and delayed rewards for each specific choice. The dashed curve corresponds to a discount function with K = 0.01. A person with this fitted value of the discount rate would choose the immediate rewards in the questions with \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K$$\\end{document}K values larger than \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0.01$$\\end{document}0.01 (bottom four hyperbolic curves), and would choose the delayed reward on the questions with \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K$$\\end{document}K values smaller than \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0.01$$\\end{document}0.01 (top five hyperbolic curves). Open grey circles represent the subjective values, V(R, d), predicted by the dashed curve for each value of delay (d) of the nine questions. Adapted from [49, 59, 71].\nWe fitted the delay discounting model using a Bayesian hierarchical (mixed-effects) logistic regression [66]. This general procedure is widely used to fit parameters in decision making tasks, see e.g. [66–69]. In brief, estimated discount rate yields a difference in subjective value between immediate and delayed rewards for each choice. A logistic sigmoid (softmax) function, \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma \\left(x\\right)=\\frac{1}{1+\\exp (-x)}$$\\end{document}σx=11+exp(−x), transforms this subjective value difference into a probability of choosing the immediate reward on each choice. We used an optimization procedure to find parameters that maximize the joint probability of each participant’s observed choices, assuming an empirical prior distribution over discount rates. This prior distribution, which is estimated using Expectation-Maximization (EM), served to regularise the inference and prevent parameters that are not well-constrained from taking on extreme values [66]. The reader is referred to [66] for the full technical details of the routine.\nTo maximize reliability, we fitted the model to the concatenated answers of both the classic and the adaptive versions of the questionnaires. We estimated the goodness-of-fit of the resulting model using McFadden’s pseudo-R², averaged across all subjects [70]. Furthermore, after fitting the model, we excluded subjects whose model accuracy is not significantly better than chance, estimated by a corresponding binomial test with a significance threshold of 0.05. Specifically, we calculated  \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p={\\sum }_{i=k}^{n}\\left(\\begin{array}{c}n\\\\ i\\end{array}\\right){0.5}^{i}{0.5}^{n-i} $$\\end{document}p=∑i=knni0.5i0.5n−i  and excluded participants for which p > 0.05.  Here, n is the number of questions in the questionnaire, k is the number of correctly classified answers and p denotes the p-value of a right-tailed binomial test, i.e., the probability of obtaining k or more correct classifications out of n by chance.\nAnalyses were performed in Matlab (R2023a) according to the pre-registered analysis plan provided in Supplementary Table 1 and also in [56]. In each analysis step reported below, we refer the reader to the corresponding analysis step from Supplementary Table 1, or indicate the step was not part of the original analysis plan. In this study we report analyses of discounting choice data. For the sake of clarity, we divide the analyses into three categories: i) prediction of relapse, ii) effect of discontinuation, and iii) discounting in remitted MDD.\nSince previous studies show that discount rates, K, are log-normally distributed [71, 72] we test for differences in log K rather than K. Unless otherwise stated, paired and independent-samples t-tests were used to compare group means. Given that each group comprised at least 30 participants, the Central Limit Theorem supports the assumption that the sampling distribution of the mean was approximately normal. Indeed, for each comparison, normality and equal variance were tested using Kolmogorov-Smirnov (MATLAB kstest function) and Bartlett tests (MATLAB vartestn test), respectively. For the few comparisons where either test rejected the null hypothesis of normality or equal variance, a non-parametric test was used: Wilcoxon Signed Rank for paired samples or Rank Sum for independent samples. We report means and standard deviations (or, where relevant, medians and interquartile ranges) for all comparisons in Supplementary Table 5.\nWe started by testing for association between discount rate and relapse by using a one-tailed two-sample t-test to test if log K at MA1 was greater in patients who relapsed than in patients who did not relapse during follow-up. This test explores the potential of baseline log K as a predictor of future relapse. We also used a one-tailed two-sample t-test to test if the change in log K between MA1 and MA2 (gain scores) differed between subjects from the MA1-D-MA2 group who relapsed during follow-up and subjects from the MA1-D-MA2 group who did not relapse during follow-up. This test examines whether a change in log K following discontinuation is associated with subsequent relapse. The tests detailed in this paragraph were not part of the pre-registered analysis plan.\nIn addition, to test for an association between time to relapse and discount rate, we used MATLAB coxphfit function to fit a Cox proportional hazards model with days to relapse as the dependent variable. We fitted two such models, with independent variables as i) log K at MA1 (Step (4) in the analysis plan), or ii) log K at both MA1 and MA2 (Step (5) in the analysis plan).\nTo examine whether discount rates can predict subsequent relapse, we fitted a logistic regression model with an L1 regularization (known as “Lasso” [73]), as implemented by the lassoglm function in Matlab, with relapse as the dependent variable and either log K at MA1 (Step (4) in the analysis plan), or both log K at MA1 and log K at MA2 as independent variables (Step (5) in the analysis plan). Consistent with the analysis plan, the model was trained on subjects from the Zurich sample, with a view to testing on the Berlin sample. We applied tenfold cross validation with stratification to optimize the value of the L1-regularization parameter.\nWe also hypothesized that discontinuation at MA1 would be associated with an increase in log K (between MA1 and MA2), assessed relative to the group who discontinued at MA2. To test for this, we fitted a linear mixed effects model using MATLAB fitlme function, with log K at both timepoints as the dependent variable, and group (i.e., MA1-D-MA2 or MA1-MA2-D), timepoint (i.e., MA1 or MA2) and [group × timepoint], as independent (fixed effect) variables (Step (2) in the analysis plan). We included a random slope term for each participant.\nWe used a one-tailed two-sample t-test to test the hypothesis that log K at MA1 was greater in patients than in controls (Step (1) in the analysis plan). We also tested for associations between log K at MA1 and scores on the various rating scales, using simple linear regression, with log K as the dependent variable. Additionally, we expressed pairwise associations between log K at MA1 and each rating scale as a Spearman correlation coefficient (Step (3) in the analysis plan).\nFinally, we tested whether log K at MA1 was associated with a change in depression (HAM-D) scores over time, independent of discontinuation (Step (6) in the analysis plan). To do so, we fitted a linear mixed effect model, wherein the dependent variable is HAM-D score (at MA1 or MA2), the independent variables (with fixed effects) are log K at MA1, timepoint (MA1 or MA2), a [log KMA1 × timepoint] interaction, discontinuation group (MA1-D-MA2 vs. MA1-MA2-D) and [discontinuation group × timepoint] interaction. We included a random slope for each participant. Here, the [log KMA1 × timepoint] interaction term expresses the extent to which a change in depression score across time depends on log K at baseline, whereas the [discontinuation group × timepoint] interaction term controls for possible confounding that results from testing on two discontinuation groups that differ in the time of withdrawal. Here we hypothesized that participants with higher baseline discounting would show less improvement in depressive symptoms across time.\nComplementary analysis methods and results that appear in the a priori analysis plan are provided in the Supplementary Material. As set out in the analysis plan, all comparisons were performed first on the Zurich sample, with a view to testing on the Berlin sample as an out-of-sample validation of predictive accuracy. However, where no significant associations between log K and the variables of interest were found in either sample, we pooled both samples to maximize power. We report these pooled analyses here.\n\n\n### Participants and study design\nData from the AIDA study has been analysed previously [51–53]. However, the delay discounting data reported here have not previously been examined. The dataset consists of: i) participants treated with antidepressant medication (ADM), who decided to discontinue their antidepressant medication independently from study participation, after being diagnosed with Major Depressive Disorder, and ii) healthy control (HC) participants matched for age, sex and education to the ADM group. Healthy controls were excluded if there was a lifetime history of DSM IV Axis I or Axis II disorders, with the sole exception of nicotine dependence. Recruitment criteria for the ADM group included: (a) at least one severe [54] or multiple depressive episodes, (b) initiation of antidepressant treatment during the last depressive episode, and (c) achieving stable remission, assessed by a score of less than 7 on the Hamilton Depression Rating Scale 17 [55] for 30 days. See [51–53] for detailed inclusion and exclusion criteria.\nAll participants gave informed written consent and received monetary compensation for their time. Ethical approval for the study was obtained from the cantonal ethics commission Zurich (BASEC: PB_2016-0.01032; KEK-ZH: 2014-0355) and the ethics commission at the Campus Charité-Mitte (EA 1/142/14), and procedures were carried out in accordance with the Declaration of Helsinki.\nAs shown in Fig. 1, participants were assessed and compared at Main Assessment 1 (MA1) to identify features characterising the remitted, medicated state. Next, patients were randomised to either discontinue their medication at MA1 (MA1-D-MA2) or enter a waiting period approximately matched to the length of discontinuation time (group MA1-MA2-D). Patients in the waiting group discontinued their ADM after Main Assessment 2 (MA2). Details of the randomisation procedure are provided in the Supporting Material. After discontinuation, all patients entered a six month follow-up (FU) period, wherein some patients experienced a relapse.Fig. 1Study Design.We recruited remitted patients treated with antidepressant medication (ADM) and healthy controls matched for age, sex and education to the patients group. Patients were assessed at Main Assessment 1 (MA1) to identify features characterizing the remitted, medicated state. Next, patients were randomized to either discontinue their medication before MA2 (bottom arm, “group MA-1-D-MA2” or enter a waiting period while continuing their ADM, matched to the length of discontinuation time (top arm, “group MA1-MA2-D”). Discounting was assessed at MA1 and MA2, to investigate the effects of discontinuation. Patients in the MA1-MA2-D discontinued their ADM after MA2. After discontinuation, all patients entered the follow-up (FU) period of 6 months, during which some patients relapsed. Numbers below each box indicate the number of subjects in that group. The numbers below each box indicate the number of subjects in the corresponding group.\nWe recruited remitted patients treated with antidepressant medication (ADM) and healthy controls matched for age, sex and education to the patients group. Patients were assessed at Main Assessment 1 (MA1) to identify features characterizing the remitted, medicated state. Next, patients were randomized to either discontinue their medication before MA2 (bottom arm, “group MA-1-D-MA2” or enter a waiting period while continuing their ADM, matched to the length of discontinuation time (top arm, “group MA1-MA2-D”). Discounting was assessed at MA1 and MA2, to investigate the effects of discontinuation. Patients in the MA1-MA2-D discontinued their ADM after MA2. After discontinuation, all patients entered the follow-up (FU) period of 6 months, during which some patients relapsed. Numbers below each box indicate the number of subjects in that group. The numbers below each box indicate the number of subjects in the corresponding group.\nThe data analysis plan for the current study was preregistered [56], and is provided in Supplementary Table 1. All participants answered rating questionnaires, among which, the measures of prior interest for the present study were Hamilton Depression Scale (HAM-D), Emotion Regulation Questionnaire (ERQ), Brief Self-Control Scale (BSCS), Daily Hassles, Satisfaction with Life Scale (SWLS), Adverse Childhood Experience (ACE), Childhood Trauma Questionnaire (CTQ), Traumatic Life Events Questionnaire (TLEQ), and the Mehrfachwahl-Wortschatz-Intelligenztest (MWT-B).\nWe also conducted a power analysis for group differences prior to the study commencement. The description of which is provided in the Supporting Material.\n\n\n### Delay discounting tasks\nDelay-discounting procedures estimate the indifference point at which a smaller but immediately available reward, r, and a larger but delayed reward, R, have approximately the same subjective value to the participant. Here, participants completed two delay discounting tasks to estimate indifference points for rewards across a range of delays. The first task was Kirby’s monetary choice questionnaire (MCQ) [57], which consists of 27 items each asking participants to choose between an immediate and a delayed reward. In the second task, participants answered an adaptive version of the questionnaire [58], wherein a discount rate is estimated after each choice the subject makes, and the next immediate and delayed rewards offered are provided from the currently estimated indifference point. At each step, this procedure elicits the most informative choice, based on a participant’s estimated discount rate. The procedure continues until a stable estimation of the indifference point is reached [58]. Including two tasks, rather than one, was intended to bolster reliability.\nIn this study, rewards were hypothetical. Although one previous study found a small reduction in discount rates for real as opposed to hypothetical rewards [59], a number of other studies report no systematic differences in discounting for real and hypothetical rewards [60–62], suggesting that assessing discounting for hypothetical rewards is a valid procedure.\n\n\n### Delay discounting model and model fitting procedure\nWe modeled the participants’ choices using a standard hyperbolic model [63]:1\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$V\\left(R,d\\right)=\\frac{R}{1+{Kd}}.$$\\end{document}VR,d=R1+Kd.\nThis equation describes the subjective value, V, of a reward, R, available after a delay d. \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K \\,{{{\\rm{is}}}}\\; {{{\\rm{a}}}}\\; {{{\\rm{discount}}}}\\; {{{\\rm{rate}}}},{{{\\rm{estimated}}}}\\; {{{\\rm{from}}}}\\; {{{\\rm{participants}}}}{{\\hbox{'}}}{{{\\rm{indifference}}}}\\; {{{\\rm{points}}}}.\\;{{{\\rm{Higher}}}}\\; {{{\\rm{values}}}}\\; {{{\\rm{of}}}}$$\\end{document}Kisadiscountrate,estimatedfromparticipants’indifferencepoints.Highervaluesof\nK reflect greater impatience and reduced tolerance for delay [52]. The hyperbolic model of delay discounting is illustrated in Fig. 2. A generalization of this hyperbolic model includes an exponent on the delay term, which adjusts the curvature of the discount curve [64, 65]. Here, since we are interested in individual differences, we omit this exponent in favour of the standard hyperbola, which captures variability in discounting with a single parameter, K.Fig. 2Hyperbolic delay discounting.Illustration of the hyperbolic model of delay discounting for a subset of nine questions from Kirby’s monetary choice questionnaire (MCQ) consisting of small amount of delayed reward (25$–35$). Each open white circle represents one of the nine questions: its X-coordinate indicates how long one would have to wait for the delayed reward (delay, d), while its Y-coordinate indicates the value of the immediate, no delay reward relative to the delayed reward (relative value, V/R). Each dotted curve represents the hyperbolic delay discount rate, K, at which a participant would be indifferent between immediate and delayed rewards for each specific choice. The dashed curve corresponds to a discount function with K = 0.01. A person with this fitted value of the discount rate would choose the immediate rewards in the questions with \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K$$\\end{document}K values larger than \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0.01$$\\end{document}0.01 (bottom four hyperbolic curves), and would choose the delayed reward on the questions with \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K$$\\end{document}K values smaller than \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0.01$$\\end{document}0.01 (top five hyperbolic curves). Open grey circles represent the subjective values, V(R, d), predicted by the dashed curve for each value of delay (d) of the nine questions. Adapted from [49, 59, 71].\nIllustration of the hyperbolic model of delay discounting for a subset of nine questions from Kirby’s monetary choice questionnaire (MCQ) consisting of small amount of delayed reward (25$–35$). Each open white circle represents one of the nine questions: its X-coordinate indicates how long one would have to wait for the delayed reward (delay, d), while its Y-coordinate indicates the value of the immediate, no delay reward relative to the delayed reward (relative value, V/R). Each dotted curve represents the hyperbolic delay discount rate, K, at which a participant would be indifferent between immediate and delayed rewards for each specific choice. The dashed curve corresponds to a discount function with K = 0.01. A person with this fitted value of the discount rate would choose the immediate rewards in the questions with \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K$$\\end{document}K values larger than \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0.01$$\\end{document}0.01 (bottom four hyperbolic curves), and would choose the delayed reward on the questions with \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K$$\\end{document}K values smaller than \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0.01$$\\end{document}0.01 (top five hyperbolic curves). Open grey circles represent the subjective values, V(R, d), predicted by the dashed curve for each value of delay (d) of the nine questions. Adapted from [49, 59, 71].\nWe fitted the delay discounting model using a Bayesian hierarchical (mixed-effects) logistic regression [66]. This general procedure is widely used to fit parameters in decision making tasks, see e.g. [66–69]. In brief, estimated discount rate yields a difference in subjective value between immediate and delayed rewards for each choice. A logistic sigmoid (softmax) function, \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma \\left(x\\right)=\\frac{1}{1+\\exp (-x)}$$\\end{document}σx=11+exp(−x), transforms this subjective value difference into a probability of choosing the immediate reward on each choice. We used an optimization procedure to find parameters that maximize the joint probability of each participant’s observed choices, assuming an empirical prior distribution over discount rates. This prior distribution, which is estimated using Expectation-Maximization (EM), served to regularise the inference and prevent parameters that are not well-constrained from taking on extreme values [66]. The reader is referred to [66] for the full technical details of the routine.\nTo maximize reliability, we fitted the model to the concatenated answers of both the classic and the adaptive versions of the questionnaires. We estimated the goodness-of-fit of the resulting model using McFadden’s pseudo-R², averaged across all subjects [70]. Furthermore, after fitting the model, we excluded subjects whose model accuracy is not significantly better than chance, estimated by a corresponding binomial test with a significance threshold of 0.05. Specifically, we calculated  \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p={\\sum }_{i=k}^{n}\\left(\\begin{array}{c}n\\\\ i\\end{array}\\right){0.5}^{i}{0.5}^{n-i} $$\\end{document}p=∑i=knni0.5i0.5n−i  and excluded participants for which p > 0.05.  Here, n is the number of questions in the questionnaire, k is the number of correctly classified answers and p denotes the p-value of a right-tailed binomial test, i.e., the probability of obtaining k or more correct classifications out of n by chance.\n\n\n### Data analysis\nAnalyses were performed in Matlab (R2023a) according to the pre-registered analysis plan provided in Supplementary Table 1 and also in [56]. In each analysis step reported below, we refer the reader to the corresponding analysis step from Supplementary Table 1, or indicate the step was not part of the original analysis plan. In this study we report analyses of discounting choice data. For the sake of clarity, we divide the analyses into three categories: i) prediction of relapse, ii) effect of discontinuation, and iii) discounting in remitted MDD.\nSince previous studies show that discount rates, K, are log-normally distributed [71, 72] we test for differences in log K rather than K. Unless otherwise stated, paired and independent-samples t-tests were used to compare group means. Given that each group comprised at least 30 participants, the Central Limit Theorem supports the assumption that the sampling distribution of the mean was approximately normal. Indeed, for each comparison, normality and equal variance were tested using Kolmogorov-Smirnov (MATLAB kstest function) and Bartlett tests (MATLAB vartestn test), respectively. For the few comparisons where either test rejected the null hypothesis of normality or equal variance, a non-parametric test was used: Wilcoxon Signed Rank for paired samples or Rank Sum for independent samples. We report means and standard deviations (or, where relevant, medians and interquartile ranges) for all comparisons in Supplementary Table 5.\n\n\n### Prediction of relapse\nWe started by testing for association between discount rate and relapse by using a one-tailed two-sample t-test to test if log K at MA1 was greater in patients who relapsed than in patients who did not relapse during follow-up. This test explores the potential of baseline log K as a predictor of future relapse. We also used a one-tailed two-sample t-test to test if the change in log K between MA1 and MA2 (gain scores) differed between subjects from the MA1-D-MA2 group who relapsed during follow-up and subjects from the MA1-D-MA2 group who did not relapse during follow-up. This test examines whether a change in log K following discontinuation is associated with subsequent relapse. The tests detailed in this paragraph were not part of the pre-registered analysis plan.\nIn addition, to test for an association between time to relapse and discount rate, we used MATLAB coxphfit function to fit a Cox proportional hazards model with days to relapse as the dependent variable. We fitted two such models, with independent variables as i) log K at MA1 (Step (4) in the analysis plan), or ii) log K at both MA1 and MA2 (Step (5) in the analysis plan).\nTo examine whether discount rates can predict subsequent relapse, we fitted a logistic regression model with an L1 regularization (known as “Lasso” [73]), as implemented by the lassoglm function in Matlab, with relapse as the dependent variable and either log K at MA1 (Step (4) in the analysis plan), or both log K at MA1 and log K at MA2 as independent variables (Step (5) in the analysis plan). Consistent with the analysis plan, the model was trained on subjects from the Zurich sample, with a view to testing on the Berlin sample. We applied tenfold cross validation with stratification to optimize the value of the L1-regularization parameter.\n\n\n### Effect of discontinuation\nWe also hypothesized that discontinuation at MA1 would be associated with an increase in log K (between MA1 and MA2), assessed relative to the group who discontinued at MA2. To test for this, we fitted a linear mixed effects model using MATLAB fitlme function, with log K at both timepoints as the dependent variable, and group (i.e., MA1-D-MA2 or MA1-MA2-D), timepoint (i.e., MA1 or MA2) and [group × timepoint], as independent (fixed effect) variables (Step (2) in the analysis plan). We included a random slope term for each participant.\n\n\n### Discounting in remitted MDD\nWe used a one-tailed two-sample t-test to test the hypothesis that log K at MA1 was greater in patients than in controls (Step (1) in the analysis plan). We also tested for associations between log K at MA1 and scores on the various rating scales, using simple linear regression, with log K as the dependent variable. Additionally, we expressed pairwise associations between log K at MA1 and each rating scale as a Spearman correlation coefficient (Step (3) in the analysis plan).\nFinally, we tested whether log K at MA1 was associated with a change in depression (HAM-D) scores over time, independent of discontinuation (Step (6) in the analysis plan). To do so, we fitted a linear mixed effect model, wherein the dependent variable is HAM-D score (at MA1 or MA2), the independent variables (with fixed effects) are log K at MA1, timepoint (MA1 or MA2), a [log KMA1 × timepoint] interaction, discontinuation group (MA1-D-MA2 vs. MA1-MA2-D) and [discontinuation group × timepoint] interaction. We included a random slope for each participant. Here, the [log KMA1 × timepoint] interaction term expresses the extent to which a change in depression score across time depends on log K at baseline, whereas the [discontinuation group × timepoint] interaction term controls for possible confounding that results from testing on two discontinuation groups that differ in the time of withdrawal. Here we hypothesized that participants with higher baseline discounting would show less improvement in depressive symptoms across time.\nComplementary analysis methods and results that appear in the a priori analysis plan are provided in the Supplementary Material. As set out in the analysis plan, all comparisons were performed first on the Zurich sample, with a view to testing on the Berlin sample as an out-of-sample validation of predictive accuracy. However, where no significant associations between log K and the variables of interest were found in either sample, we pooled both samples to maximize power. We report these pooled analyses here.\n\n\n### Results\nOut of 104 patients with remitted MDD and 57 controls who were initially recruited, 97 patients (71 from Zurich and 26 from Berlin; 77% female, average age 34.78) and 54 controls (32 from Zurich and 22 from Berlin; 70% female, average age 33.52) answered the discounting questionnaire at MA1. 47 and 50 patients were randomized at MA1 to the discontinuation (MA1-D-MA2) and continuation group (MA1-MA2-D), respectively. 10 patients dropped out before MA2 and 7 more patients dropped during the follow-up period. The 17 dropouts were excluded from the prediction of relapse analysis. Among the included patients, 52 remained well (65%) and 28 (35%) relapsed during the follow-up period. The numbers of participants in each group are also indicated in Fig. 1. At baseline, HAM-D scores in the remitted patient group, although below the clinical threshold for MDD, were significantly higher than those in the control group (HAM-D controls mean = 0.38, median = 0, HAM-D patients mean = 1.81, median = 1; two-sample, two-tailed t-test t(147) = 5.15, p < 0.001; Wilcoxon rank sum test p < 0.001).\nModel accuracy met the (binomial test) accuracy criterion described above for all participants, and therefore no participants were excluded. The average model accuracy was 85%; mean McFadden’s pseudo-\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${R}^{2}$$\\end{document}R2 across subjects was 0.59, indicating a good fit to the data. Discount rates obtained from the adaptive discounting questionnaire and the Kirby MCQ were only moderately correlated (Spearman ρ = 0.32, p < 0.001).\nIn addition, no significant associations were found between log K at baseline and any possible confounding factors tested. The details and results are provided in Supplementary Table 2.\nWe found no significant difference in log K at MA1 between subjects treated with ADM who relapsed during follow-up and subjects treated with ADM who did not relapse (t(78) = 0.44, p > 0.25,two-tailed two-sample; Cohen’s d = 0.10). Furthermore, a change in log K following discontinuation (i.e., between MA1 and MA2 amongst the MA1-D-MA2 group), did not differ significantly between participants who subsequently relapsed and those who did not relapse (t(37) = 0.58, p > 0.25, one-tailed; Cohen’s d = 0.20), see Fig. 3. In a Cox proportional hazards regression model, including log K at both timepoints, neither log KMA1 nor log KMA2 were significantly associated with days-to-relapse (Coefficient log KMA1 = −0.02, p > 0.25; coefficient log KMA2 = −0.08, p > 0.25), nor was log KMA1 associated with relapse when entered into a separate regression model (Coefficient = −0.08, p > 0.25).Fig. 3Effect sizes for group differences in log K.Cohen’s d effect size, for various group comparisons. The top bar shows the comparison of log K at MA1 between controls and patients, where the effect size in this case indicates that the average of log K in the Patients group (at both sites) at MA1 is greater than the average of log K in the Controls group at MA1. The second bar from above shows the comparison of log K at MA1 between patients who subsequently relapsed and patients who did not, where the effect size in this case indicates that the average of log K in non-relapsers at MA1 is greater than the average of log K in relapsers at MA1. The third bar shows the comparison of the change in log K between the two timepoints (gain scores), between patients who discontinued their treatment at MA1 (MA1-D-MA2) and patients who continued their treatment until MA2 (MA1-MA2-D), where the effect size indicates that the average of gain scores in the MA1-D-MA2 group is greater than the average of gain scores in the MA1-MA2-D group. The bottom bar shows the comparison of the change in log K between the two timepoints (gain scores), between patients from the MA1-D-MA2 group who subsequently relapsed and patients from the MA1-D-MA2 group who did not, where the effect size indicates that the average of gain scores in the non-relapsers group was greater than the average of gain scores in the relapsers group. Error bars represent 95% confidence interval for Cohen’s d effect size, estimated using MATLAB meanEffectSize function. Group difference p-value: * 0.01 0.25). In other words, discontinuation did not significantly alter a change in log K across time. Main effects of timepoint and group were also small and non-significant (\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{group}}$$\\end{document}βgroup = −0.05, t(180) = −0.10, p > 0.25 ; \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{timepoint}}$$\\end{document}βtimepoint = 0.10, t(180) = 0.56, p > 0.25).\nWe further explored this null finding in a post hoc analysis, by performing a one-tailed two-sample t-test on log K gain scores to test whether log K increased more in patients who discontinued at MA1 (MA1-D-MA2) than in patients who discontinued at MA2 (MA1-MA2-D). To prevent error accumulation due to the additivity of noise, in model fitting, the difference between log K at MA1 and log K at MA2 was estimated concurrently with log K at MA1. Again, we found no significant difference in the change in log K between MA1 and MA2, among the MA1-D-MA2 group compared with the MA1-MA2-D group (t(82) = 0.19, p > 0.25; Cohen’s d = 0.04), also indicated in Fig. 3.\nA possible explanation for these null results would be that our delay discounting measure was unreliable. If this were the case, we would expect no consistent relationship between discounting at MA1 and MA2. Contrary to this idea however, across all patients we found a moderate correlation between log K at the two timepoints (r = 0.72, p < 0.001). Similar test-retest correlations were observed in both the MA1-D-MA2 (r = 0.80, p < 0.001) and MA1-MA2-D groups (r = 0.65, p < 0.001). These results indicate that the rank order of discounting across participants was moderately stable over time, supporting the reliability of our discounting measure.\nA further possible explanation for observing no effect of discontinuation on impulsivity would be that discontinuation produced no significant withdrawal syndrome in the study participants. Against this, the MA1-D-MA2 group exhibited a statistically significant increase in depressive symptoms following discontinuation (MA1 HAM-D mean = 1.65, median = 1; MA2 HAM-D mean = 3.16, median = 3; t(39) = 4.39, p < 0.001, two-tailed; Wilcoxon signed rank p < 0.001). No such symptom change was observed in the MA1-MA2-D group, who did not discontinue medication until after the second timepoint (MA1 HAM-D mean = 1.98, median = 2; MA2 HAM-D mean = 2.18, median = 2; t(40) = 0.34, p = 0.733, two-tailed; Wilcoxon signed rank p = 0.610). Furthermore, symptom change between the two timepoints in the MA1-D-MA2 group was significantly greater than that in the MA1-MA2-D group (two-sample t-test, t(79) = 2.77, p = 0.007, two-tailed; Wilcoxon rank sum p = 0.013). These findings indicate a detectable effect of discontinuation.\nGroup comparison of log K between healthy controls and patients with remitted MDD (treated with ADM) at MA1 revealed significantly higher discount rates in the patient group (t(149) = 2.03 and p = 0.022, one-tailed; Cohen’s d = 0.34), also indicated in Fig. 3. Notably both groups showed low levels of impulsivity, and the absolute difference in K between the two groups was small. Mean K in the remitted MDD group was 0.0065, corresponding to indifference between a reward of 75 euros received in 20 days and an immediate reward of 66 euros. Mean K in the control group was 0.0037, corresponding to indifference between a reward of 75 euros received in 20 days and an immediate reward of 70 euros.\nAs shown in Fig. 4, depressive symptoms (measured by the HAM-D scale) were significantly correlated with baseline discount rate, log KMA1 (Spearman ρ = 0.24, p = 0.003), an association which survived Bonferroni correction for multiple comparisons (p = 0.022, corrected for 8 comparisons), and was also present when testing only on the patients’ group (Spearman ρ = 0.23, p = 0.025). Other questionnaire instruments did not exhibit significant correlations with log KMA1 (Fig. 4). We note that baseline discount rate showed a significant correlation with two subscales of the CTQ questionnaire, namely CTQ-physical abuse (Spearman ρ = 0.18, p = 0.023) and CTQ-emotional neglect (Spearman ρ = 0.16, p = 0.049). See Supplementary Figure S2 for the comparisons with other questionnaire subscales. When all questionnaire variables were entered into a linear regression model with log KMA1 as the dependent variable, only HAM-D emerged as a significant explanatory variable (coefficient estimate = 0.19, t(142) = 2.51, p = 0.013). Coefficients and t-statistics for the remaining rating scales are provided in Supplementary Table 3.Fig. 4Correlations between log K at MA1 and rating scales.HAM-D Hamilton Depression Scale, ERQ Emotion Regulation Questionnaire (ERQ), BSCS Brief Self-Control Scale, SWLS Satisfaction with Life Scale, ACE Adverse Childhood Experience, CTQ Childhood Trauma Questionnaire, TLEQ Traumatic Life Events Questionnaire, MWTB Mehrfachwahl-Wortschatz-Intelligenztest. Error bars represent 95% confidence interval for Spearman’s correlation coefficient estimated using 10,000 bootstrap iterations. Group difference p-value: * 0.01 0.25,two-tailed two-sample; Cohen’s d = 0.10). Furthermore, a change in log K following discontinuation (i.e., between MA1 and MA2 amongst the MA1-D-MA2 group), did not differ significantly between participants who subsequently relapsed and those who did not relapse (t(37) = 0.58, p > 0.25, one-tailed; Cohen’s d = 0.20), see Fig. 3. In a Cox proportional hazards regression model, including log K at both timepoints, neither log KMA1 nor log KMA2 were significantly associated with days-to-relapse (Coefficient log KMA1 = −0.02, p > 0.25; coefficient log KMA2 = −0.08, p > 0.25), nor was log KMA1 associated with relapse when entered into a separate regression model (Coefficient = −0.08, p > 0.25).Fig. 3Effect sizes for group differences in log K.Cohen’s d effect size, for various group comparisons. The top bar shows the comparison of log K at MA1 between controls and patients, where the effect size in this case indicates that the average of log K in the Patients group (at both sites) at MA1 is greater than the average of log K in the Controls group at MA1. The second bar from above shows the comparison of log K at MA1 between patients who subsequently relapsed and patients who did not, where the effect size in this case indicates that the average of log K in non-relapsers at MA1 is greater than the average of log K in relapsers at MA1. The third bar shows the comparison of the change in log K between the two timepoints (gain scores), between patients who discontinued their treatment at MA1 (MA1-D-MA2) and patients who continued their treatment until MA2 (MA1-MA2-D), where the effect size indicates that the average of gain scores in the MA1-D-MA2 group is greater than the average of gain scores in the MA1-MA2-D group. The bottom bar shows the comparison of the change in log K between the two timepoints (gain scores), between patients from the MA1-D-MA2 group who subsequently relapsed and patients from the MA1-D-MA2 group who did not, where the effect size indicates that the average of gain scores in the non-relapsers group was greater than the average of gain scores in the relapsers group. Error bars represent 95% confidence interval for Cohen’s d effect size, estimated using MATLAB meanEffectSize function. Group difference p-value: * 0.01 0.25). In other words, discontinuation did not significantly alter a change in log K across time. Main effects of timepoint and group were also small and non-significant (\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{group}}$$\\end{document}βgroup = −0.05, t(180) = −0.10, p > 0.25 ; \\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{timepoint}}$$\\end{document}βtimepoint = 0.10, t(180) = 0.56, p > 0.25).\nWe further explored this null finding in a post hoc analysis, by performing a one-tailed two-sample t-test on log K gain scores to test whether log K increased more in patients who discontinued at MA1 (MA1-D-MA2) than in patients who discontinued at MA2 (MA1-MA2-D). To prevent error accumulation due to the additivity of noise, in model fitting, the difference between log K at MA1 and log K at MA2 was estimated concurrently with log K at MA1. Again, we found no significant difference in the change in log K between MA1 and MA2, among the MA1-D-MA2 group compared with the MA1-MA2-D group (t(82) = 0.19, p > 0.25; Cohen’s d = 0.04), also indicated in Fig. 3.\nA possible explanation for these null results would be that our delay discounting measure was unreliable. If this were the case, we would expect no consistent relationship between discounting at MA1 and MA2. Contrary to this idea however, across all patients we found a moderate correlation between log K at the two timepoints (r = 0.72, p < 0.001). Similar test-retest correlations were observed in both the MA1-D-MA2 (r = 0.80, p < 0.001) and MA1-MA2-D groups (r = 0.65, p < 0.001). These results indicate that the rank order of discounting across participants was moderately stable over time, supporting the reliability of our discounting measure.\nA further possible explanation for observing no effect of discontinuation on impulsivity would be that discontinuation produced no significant withdrawal syndrome in the study participants. Against this, the MA1-D-MA2 group exhibited a statistically significant increase in depressive symptoms following discontinuation (MA1 HAM-D mean = 1.65, median = 1; MA2 HAM-D mean = 3.16, median = 3; t(39) = 4.39, p < 0.001, two-tailed; Wilcoxon signed rank p < 0.001). No such symptom change was observed in the MA1-MA2-D group, who did not discontinue medication until after the second timepoint (MA1 HAM-D mean = 1.98, median = 2; MA2 HAM-D mean = 2.18, median = 2; t(40) = 0.34, p = 0.733, two-tailed; Wilcoxon signed rank p = 0.610). Furthermore, symptom change between the two timepoints in the MA1-D-MA2 group was significantly greater than that in the MA1-MA2-D group (two-sample t-test, t(79) = 2.77, p = 0.007, two-tailed; Wilcoxon rank sum p = 0.013). These findings indicate a detectable effect of discontinuation.\n\n\n### Discounting in remitted MDD\nGroup comparison of log K between healthy controls and patients with remitted MDD (treated with ADM) at MA1 revealed significantly higher discount rates in the patient group (t(149) = 2.03 and p = 0.022, one-tailed; Cohen’s d = 0.34), also indicated in Fig. 3. Notably both groups showed low levels of impulsivity, and the absolute difference in K between the two groups was small. Mean K in the remitted MDD group was 0.0065, corresponding to indifference between a reward of 75 euros received in 20 days and an immediate reward of 66 euros. Mean K in the control group was 0.0037, corresponding to indifference between a reward of 75 euros received in 20 days and an immediate reward of 70 euros.\nAs shown in Fig. 4, depressive symptoms (measured by the HAM-D scale) were significantly correlated with baseline discount rate, log KMA1 (Spearman ρ = 0.24, p = 0.003), an association which survived Bonferroni correction for multiple comparisons (p = 0.022, corrected for 8 comparisons), and was also present when testing only on the patients’ group (Spearman ρ = 0.23, p = 0.025). Other questionnaire instruments did not exhibit significant correlations with log KMA1 (Fig. 4). We note that baseline discount rate showed a significant correlation with two subscales of the CTQ questionnaire, namely CTQ-physical abuse (Spearman ρ = 0.18, p = 0.023) and CTQ-emotional neglect (Spearman ρ = 0.16, p = 0.049). See Supplementary Figure S2 for the comparisons with other questionnaire subscales. When all questionnaire variables were entered into a linear regression model with log KMA1 as the dependent variable, only HAM-D emerged as a significant explanatory variable (coefficient estimate = 0.19, t(142) = 2.51, p = 0.013). Coefficients and t-statistics for the remaining rating scales are provided in Supplementary Table 3.Fig. 4Correlations between log K at MA1 and rating scales.HAM-D Hamilton Depression Scale, ERQ Emotion Regulation Questionnaire (ERQ), BSCS Brief Self-Control Scale, SWLS Satisfaction with Life Scale, ACE Adverse Childhood Experience, CTQ Childhood Trauma Questionnaire, TLEQ Traumatic Life Events Questionnaire, MWTB Mehrfachwahl-Wortschatz-Intelligenztest. Error bars represent 95% confidence interval for Spearman’s correlation coefficient estimated using 10,000 bootstrap iterations. Group difference p-value: * 0.01