Economic Evaluation of an Internet-Based Preventive Cognitive Therapy With Minimal Therapist Support for Recurrent Depression: Randomized Controlled Trial.

BACKGROUND: Major depressive disorder (MDD) is highly recurrent and has a significant disease burden. Although the effectiveness of internet-based interventions has been established for the treatment of acute MDD, little is known about their cost effectiveness, especially in recurrent MDD. OBJECTIVES: Our aim was to evaluate the cost effectiveness and cost utility of an internet-based relapse prevention program (mobile cognitive therapy, M-CT). METHODS: The economic evaluation was performed alongside a single-blind parallel group randomized controlled trial. Participants were recruited via media, general practitioners, and mental health care institutions. In total, 288 remitted individuals with a history of recurrent depression were eligible, of whom 264 were randomly allocated to M-CT with minimal therapist support added to treatment as usual (TAU) or TAU alone. M-CT comprised 8 online lessons, and participants were advised to complete 1 lesson per week. The economic evaluation was performed from a societal perspective with a 24-month time horizon. The health outcomes were number of depression-free days according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV) criteria assessed with the Structured Clinical Interview for DSM-IV axis I disorders by blinded interviewers after 3, 12, and 24 months. Quality-adjusted life years (QALYs) were self-assessed with the three level version of the EuroQol Five Dimensional Questionnaire (EQ-5D-3L). Costs were assessed with the Trimbos and Institute for Medical Technology Assessment Questionnaire on Costs Associated with Psychiatric Illness (TiC-P). Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were displayed to assess the probability that M-CT is cost effective compared to TAU. RESULTS: Mean total costs over 24 months were €8298 (US $9415) for M-CT and €7296 (US $8278) for TAU. No statistically significant differences were found between M-CT and TAU regarding depression-free days and QALYs (P=.37 and P=.92, respectively). The incremental costs were €179 (US $203) per depression-free day and €230,816 (US $261,875) per QALY. The cost-effectiveness acceptability curves suggested that for depression-free days, high investments have to be made to reach an acceptable probability that M-CT is cost effective compared to TAU. Regarding QALYs, considerable investments have to be made but the probability that M-CT is cost effective compared to TAU does not rise above 40%. CONCLUSIONS: The results suggest that adding M-CT to TAU is not effective and cost effective compared to TAU alone. Adherence rates were similar to other studies and therefore do not explain this finding. The participants scarcely booked additional therapist support, resulting in 17.3 minutes of mean total therapist support. More studies are needed to examine the cost effectiveness of internet-based interventions with respect to long-term outcomes and the role and optimal dosage of therapist support. Overall, more research is needed on scalable and cost-effective interventions that can reduce the burden of recurrent MDD. TRIAL REGISTRATION: Netherlands Trial Register NTR2503; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2503 (Archived by WebCite at http://www.webcitation.org/73aBn41r3).

Exploring the relation between visual mental imagery and affect in the daily life of previously depressed and never depressed individuals.

Previously depressed individuals experience disturbances in affect. Affective disturbances may be related to visual mental imagery, given that imagery-based processing of emotional stimuli causes stronger affective responses than verbal processing in experimental laboratory studies. However, the role of imagery-based processing in everyday life is unknown. This study assessed mental imagery in the daily life of previously and never depressed individuals. Higher levels of visual mental imagery was hypothesised to be associated with more affective reactivity to both negatively and positively valenced mental representations. This study was the first to explore mental imagery in daily life using experience sampling methodology. Previously depressed (n = 10) and matched never depressed (n = 11) individuals participated in this study. Momentary affect and imagery-based processing were assessed using the "Imagine your mood" smartphone application. Participants recorded on average 136 momentary reports over a period of 8 weeks. The expected association between visual mental imagery and affective reactivity was not found. Unexpectedly, in both previously and never depressed individuals, higher levels of imagery-based processing of mental representations in daily life were significantly associated with better momentary mood and more positive affect, regardless of valence. The causality of effects remains to be examined in future studies.

Beliefs about the causes of depression and recovery and their impact on adherence, dosage, and successful tapering of antidepressants.

BACKGROUND: Continuation of antidepressant medication (ADM) after remission is widely used to prevent depressive relapse/recurrence. Little is known about predictors of ADM use in terms of adherence, dosage, and successful tapering. The current study aimed to explore beliefs about the causes of depression and recovery (i.e., causal beliefs) and to examine whether they predict ADM use. METHODS: The data were drawn from a controlled trial and an extension of this trial with additional experience sampling. In total, 289 remitted patients with recurrent depression (ADM ≥ 6 months) were randomly assigned to Preventive Cognitive Therapy (PCT) with ADM tapering, PCT with maintenance ADM, or maintenance ADM alone. Adherence, ADM dosage, and causal beliefs regarding the first and last depressive episodes were explored via questionnaires. RESULTS: Most patients mentioned stressful life events as cause of depression, although more patients tended to endorse external causes for the first episode and internal causes for the last episode. ADM was most often mentioned as helpful during recovery from both episodes. Over half of all patients were adherent and under half of the patients in the tapering condition were able to complete the taper. Causal beliefs did not predict ADM use. CONCLUSIONS: The results suggest that causal beliefs play little role in the use of maintenance ADM. More information is needed on factors contributing to successful tapering. The results must be interpreted with caution as this is not a naturalistic study and the results might be biased toward a more favorable view regarding ADM.

Differential impact of preventive cognitive therapy while tapering antidepressants versus maintenance antidepressant treatment on affect fluctuations and individual affect networks and impact on relapse: a secondary analysis of a randomised controlled trial.

Background: There is an urgent need to better understand and prevent relapse in major depressive disorder (MDD). We explored the differential impact of various MDD relapse prevention strategies (pharmacological and/or psychological) on affect fluctuations and individual affect networks in a randomised setting, and their predictive value for relapse. Methods: We did a secondary analysis using experience sampling methodology (ESM) data from individuals with remitted recurrent depression that was collected alongside a randomised controlled trial that ran in the Netherlands, comparing: (I) tapering antidepressants while receiving preventive cognitive therapy (PCT), (II) combining antidepressants with PCT, or (III) continuing antidepressants without PCT, for the prevention of depressive relapse, as well as ESM data from 11 healthy controls. Participants had multiple past depressive episodes, but were remitted for at least 8 weeks and on antidepressants for at least six months. Exclusion criteria were: current (hypo)mania, current alcohol or drug abuse, anxiety disorder that required treatment, psychological treatment more than twice per month, a diagnosis of organic brain damage, or a history of bipolar disorder or psychosis. Fluctuations (within-person variance, root mean square of successive differences, autocorrelation) in negative and positive affect were calculated. Changes in individual affect networks during treatment were modelled using time-varying vector autoregression, both with and without applying regularisation. We explored whether affect fluctuations or changes in affect networks over time differed between treatment conditions or relapse outcomes, and predicted relapse during 2-year follow-up. This ESM study was registered at ISRCTN registry, ISRCTN15472145. Findings: Between Jan 1, 2014, and Jan 31, 2015, 72 study participants were recruited, 42 of whom were included in the analyses. We found no indication that affect fluctuations differed between treatment groups, nor that they predicted relapse. We observed large individual differences in affect network structure across participants (irrespective of treatment or relapse status) and in healthy controls. We found no indication of group-level differences in how much networks changed over time, nor that changes in networks over time predicted time to relapse (regularised models: hazard ratios [HR] 1063, 95% CI <0.0001->10 000, p = 0.65; non-regularised models: HR 2.54, 95% CI 0.23-28.7, p = 0.45) or occurrence of relapse (regularised models: odds ratios [OR] 22.84, 95% CI <0.0001->10 000, p = 0.90; non-regularised models: OR 7.57, 95% CI 0.07-3709.54, p = 0.44) during complete follow-up. Interpretation: Our findings should be interpreted with caution, given the exploratory nature of this study and wide confidence intervals. While group-level differences in affect dynamics cannot be ruled out due to low statistical power, visual inspection of individual affect networks also revealed no meaningful patterns in relation to MDD relapse. More studies are needed to assess whether affect dynamics as informed by ESM may predict relapse or guide personalisation of MDD relapse prevention in daily practice. Funding: The Netherlands Organisation for Health Research and Development, Dutch Research Council, University of Amsterdam.

Psychological theories of depressive relapse and recurrence: A systematic review and meta-analysis of prospective studies.

Psychological factors hypothesized to account for relapse of major depressive disorder (MDD) roughly originate from five main theories: Cognitive, diathesis-stress, behavioural, psychodynamic, and personality-based. In a meta-analysis we investigated prospective, longitudinal evidence for these leading psychological theories and their factors in relation to depressive relapse. Included studies needed to establish history of MDD and prospective depressive relapse through a clinical interview, have a longitudinal and prospective design, and measure at least one theory-derived factor before relapse. We identified 66 eligible articles out of 43,586 records published up to November 2018. Pooled odds ratios (OR) indicated a significant relationship between the cognitive, behavioural, and personality-based theories and depressive relapse (cognitive: k = 17, OR = 1.24, 95% CI = 1.10-1.40; behavioural, k = 8, OR = 1.15, 95% CI = 1.05-1.25; personality: k = 12, OR = 1.26, 95% CI = 1.02-1.54), but not for the psychodynamic theories (k = 4, OR = 1.29, 95% CI = 0.83-1.99). Pooled hazard ratios of the theories were not significant. There were no articles identified for the diathesis-stress theories. To conclude, there is a restricted number of prospective studies, and some evidence that the cognitive, behavioural, and personality-based theories indeed partially account for depressive relapse.

Cost-effectiveness, cost-utility and the budget impact of antidepressants versus preventive cognitive therapy with or without tapering of antidepressants.

BACKGROUND: As depression has a recurrent course, relapse and recurrence prevention is essential.AimsIn our randomised controlled trial (registered with the Nederlands trial register, identifier: NTR1907), we found that adding preventive cognitive therapy (PCT) to maintenance antidepressants (PCT+AD) yielded substantial protective effects versus antidepressants only in individuals with recurrent depression. Antidepressants were not superior to PCT while tapering antidepressants (PCT/-AD). To inform decision-makers on treatment allocation, we present the corresponding cost-effectiveness, cost-utility and budget impact. METHOD: Data were analysed (n = 289) using a societal perspective with 24-months of follow-up, with depression-free days and quality-adjusted life years (QALYs) as health outcomes. Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were derived to provide information about cost-effectiveness. The budget impact was examined with a health economic simulation model. RESULTS: Mean total costs over 24 months were €6814, €10 264 and €13 282 for AD+PCT, antidepressants only and PCT/-AD, respectively. Compared with antidepressants only, PCT+AD resulted in significant improvements in depression-free days but not QALYs. Health gains did not significantly favour antidepressants only versus PCT/-AD. High probabilities were found that PCT+AD versus antidepressants only and antidepressants only versus PCT/-AD were dominant with low willingness-to-pay thresholds. The budget impact analysis showed decreased societal costs for PCT+AD versus antidepressants only and for antidepressants only versus PCT/-AD. CONCLUSIONS: Adding PCT to antidepressants is cost-effective over 24 months and PCT with guided tapering of antidepressants in long-term users might result in extra costs. Future studies examining costs and effects of antidepressants versus psychological interventions over a longer period may identify a break-even point where PCT/-AD will become cost-effective.Declaration of interestC.L.H.B. is co-editor of PLOS One and receives no honorarium for this role. She is also co-developer of the Dutch multidisciplinary clinical guideline for anxiety and depression, for which she receives no remuneration. She is a member of the scientific advisory board of the National Insure Institute, for which she receives an honorarium, although this role has no direct relation to this study. C.L.H.B. has presented keynote addresses at conferences, such as the European Psychiatry Association and the European Conference Association, for which she sometimes receives an honorarium. She has presented clinical training workshops, some including a fee. She receives royalties from her books and co-edited books and she developed preventive cognitive therapy on the basis of the cognitive model of A. T. Beck. W.A.N. has received grants from the Netherlands Organisation for Health Research and Development and the European Union and honoraria and speakers' fees from Lundbeck and Aristo Pharma, and has served as a consultant for Daleco Pharma.

Development and validation of a clinical prediction tool to estimate the individual risk of depressive relapse or recurrence in individuals with recurrent depression.

OBJECTIVES: Many studies examined predictors of depressive relapse/recurrence but no simple tool based on well-established risk factors is available that estimates the risk within an individual. We developed and validated such a prediction tool in remitted recurrently depressed individuals. METHODS: The tool was developed using data (n = 235) from a pragmatic randomised controlled trial in remitted recurrently depressed participants and externally validated using data (n = 209) from a similar randomised controlled trial of remitted recurrently depressed participants using maintenance antidepressants. Cox regression was used with time to relapse/recurrence within 2 years as outcome and well-established risk factors as predictors. Performance measures and absolute risk scores were calculated, a practically applicable risk score was created, and the tool was externally validated. RESULTS: The 2-year cumulative proportion relapse/recurrence was 46.2% in the validation dataset. The tool included number of previous depressive episodes, residual depressive symptoms, severity of the last depressive episode, and treatment. The C-statistic and calibration slope were 0.56 and 0.81 respectively. The tool stratified participants into relapse/recurrence risk classes of 37%, 55%, and 72%. The C-statistic and calibration slope in the external validation were 0.59 and 0.56 respectively, and Kaplan Meier curves showed that the tool could differentiate between risk classes. CONCLUSIONS: This is the first study that developed a simple prediction tool based on well-established risk factors of depressive relapse/recurrence, estimating the individual risk. Since the overall performance of the model was poor, more studies are needed to enhance the performance before recommending implementation into clinical practice.

Effectiveness of preventive cognitive therapy while tapering antidepressants versus maintenance antidepressant treatment versus their combination in prevention of depressive relapse or recurrence (DRD study): a three-group, multicentre, randomised controlled trial.

BACKGROUND: Keeping individuals on antidepressants after remission or recovery of major depressive disorder is a common strategy to prevent relapse or recurrence. Preventive cognitive therapy (PCT) has been proposed as an alternative to maintenance antidepressant treatment, but whether its addition would allow tapering of antidepressants or enhance the efficacy of maintenance antidepressant treatment is unclear. We aimed to compare the effectiveness of antidepressants alone, with PCT while tapering off antidepressants, or PCT added to antidepressants in the prevention of relapse and recurrence. METHODS: In this single-blind, multicentre, parallel, three-group, randomised controlled trial, individuals recruited by general practitioners, pharmacists, secondary mental health care, or media were randomly assigned (10:10:8) to PCT and antidepressants, antidepressants alone, or PCT with tapering of antidepressants, using computer-generated randomised allocation stratified for number of previous depressive episodes and type of care. Eligible participants had previously experienced at least two depressive episodes and were in remission or recovery on antidepressants, which they had been receiving for at least the past 6 months. Exclusion criteria were current mania or hypomania, a history of bipolar disorder, any history of psychosis, current alcohol or drug abuse, an anxiety disorder that requires treatment, psychological treatment more than twice a month, and a diagnosis of organic brain damage. The primary outcome was time-related proportion of individuals with depressive relapse or recurrence in the intention-to-treat population, assessed four times in 24 months. Assessors were masked to treatment allocation, whereas physicians and participants could not be masked. This trial is registered with the Netherlands Trial Register, number NTR1907. FINDINGS: Between July 14, 2009, and April 30, 2015, 2486 participants were assessed for eligibility and 289 were randomly assigned to PCT and antidepressant (n=104), antidepressant alone (n=100), or PCT with tapering of antidepressant (n=85). The overall log-rank test was significant (p=0·014). Antidepressants alone were not superior to PCT while tapering off antidepressants in terms of the risk of relapse or recurrence (hazard ratio [HR] 0·86, 95% CI 0·56-1·32; p=0·502). Adding PCT to antidepressant treatment resulted in a 41% relative risk reduction compared with antidepressants alone (0·59, 0·38-0·94; p=0·026). There were two suicide attempts (one in the antidepressants alone group and one in the PCT with tapering of antidepressants group) and one death (in the PCT and antidepressants group) not related to the interventions during the 24 months' follow-up. INTERPRETATION: Maintenance antidepressant treatment is not superior to PCT after recovery, whereas adding PCT to antidepressant treatment after recovery is superior to antidepressants alone. PCT should be offered to recurrently depressed individuals on antidepressants and to individuals who wish to stop antidepressants after recovery. FUNDING: The Netherlands Organisation for Health Research and Development.

Imagine your mood: Study design and protocol of a randomized controlled micro-trial using app-based experience sampling methodology to explore processes of change during relapse prevention interventions for recurrent depression.

BACKGROUND: Relapse prevention strategies include continuation of antidepressant medication and preventive psychological interventions. This study aims to gain understanding that may inform tailoring of relapse prevention to individual differences, to improve their effects. Such treatment personalization may be based on repeated assessments within one individual, using experience sampling methodology. As a first step towards informing decisions based on this methodology, insight is needed in individual differences in risk of relapse and response to treatment, and how relapse prevention strategies may differentially target vulnerability for relapse. METHODS: The smartphone application 'Imagine your mood' has been developed specifically for this study to assess emotions, imagery, cognitions, and behaviors in daily life. Parallel to the randomized controlled trial 'Disrupting the rhythm of depression', 45 remitted recurrently depressed individuals taking continuation antidepressant medication will be randomly assigned to either continuing antidepressant medication (n = 15), continuing antidepressant medication combined with an eight-session preventive cognitive therapy (n = 15), or tapering of antidepressant medication in combination with preventive cognitive therapy (n = 15). Relapse and return of depressive symptomatology over a 24-month follow-up will be assessed. Additionally, matched never depressed individuals (n = 15) will be recruited as controls. DISCUSSION: This innovative study combines the strengths of a randomized controlled trial and experience sampling methodology in a micro-trial to explore individual differences in risk of relapse and what works for whom to prevent relapse. Results may ultimately pave the way for therapists to tailor relapse prevention strategies to individual (affective) vulnerability. TRIAL REGISTRATION: ISRCTN15472145, retrospectively registered.