A cognitive remediation training for young adults with psychotic disorders to support their participation in education - study protocol for a pilot randomized controlled trial.

BACKGROUND: Most severe mental disorders have their onset between the age of 17 and 27, a time when many young adults begin participating in secondary or post-secondary education. The cognitive deficits typically associated with psychiatric disorders, especially psychotic disorders, increase the risk of leaving school early, which can lead to a reduction in employment opportunities later on in life and, in turn, a poorer long-term prognosis. Therefore, specific interventions aiming to improve these cognitive functions are needed. Cognitive remediation (CR) aims to improve cognitive functioning and may increase real-world functioning in educational performance. This study aims to examine the feasibility and applicability of a CR training named Mindset for students with psychotic disorders in the Netherlands. METHODS/DESIGN: Sixty students diagnosed with a psychotic disorder and currently reporting cognitive deficits will be included from four Dutch Mental Health Care institutes. Half of the participants (N = 30) will be randomly assigned to the CR training consisting of twelve, individual, weekly 1-h meetings. The other half will be assigned to an active control condition consisting of twelve weekly assignments that will be sent by email aiming to improve school performance. Students will be evaluated at baseline (T0), directly after finishing the CR training or control intervention (T1), and 6 months later (T2). Treatment feasibility will be the primary outcome, using evaluation forms, interviews with trainers and participants, number of study drop outs, and patient eligibility and recruitment rates. School functioning, cognitive functioning, and strategy use will also be assessed to get a preliminary idea of the potential effectiveness of the intervention. DISCUSSION: The CR training in this study will provide real-world examples and exercises aimed to teach useful strategies to cope with the cognitive deficits experienced by students with psychotic disorders. Furthermore, since students with other psychiatric disorders might also experience cognitive deficits, the results of this study may also provide some further implications for future studies on the effect of this CR training for students with these disorders. TRIAL REGISTRATION: The study was registered with Trialregister.nl, no. NL6590 (NTR6764), date registered: September 7, 2017. Register name: Mindset. A cognitive rehabilitation training for young adults with psychotic spectrum disorder in an educational setting: A pilot study.Protocol version: 3, date December 23, 2019.

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.

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.

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.

Cognitive reactivity, self-depressed associations, and the recurrence of depression.

BACKGROUND: Mixed evidence exists regarding the role of cognitive reactivity (CR; cognitive responsivity to a negative mood) as a risk factor for recurrences of depression. One explanation for the mixed evidence may lie in the number of previous depressive episodes. Heightened CR may be especially relevant as a risk factor for the development of multiple depressive episodes and less so for a single depressive episode. In addition, it is theoretically plausible but not yet tested that the relationship between CR and number of episodes is moderated by the strength of automatic depression-related self-associations. AIM: To investigate (i) the strength of CR in remitted depressed individuals with a history of a single vs. multiple episodes, and (ii) the potentially moderating role of automatic negative self-associations in the relationship between the number of episodes and CR. METHOD: Cross-sectional analysis of data obtained in a cohort study (Study 1) and during baseline assessments in two clinical trials (Study 2). Study 1 used data from the Netherlands Study of Depression and Anxiety (NESDA) and compared never-depressed participants (n=901) with remitted participants with either a single (n=336) or at least 2 previous episodes (n=273). Study 2 included only remitted participants with at least two previous episodes (n=273). The Leiden Index of Depression Sensitivity Revised (LEIDS-R) was used to index CR and an Implicit Association Test (IAT) to measure implicit self-associations. RESULTS: In Study 1, remitted depressed participants with multiple episodes had significantly higher CR than those with a single or no previous episode. The remitted individuals with multiple episodes of Study 2 had even higher CR scores than those of Study 1. Within the group of individuals with multiple episodes, CR was not heightened as a function of the number of episodes, even if individual differences in automatic negative self-associations were taken into account. LIMITATIONS: The study employed a cross-sectional design, which precludes a firm conclusion with regard to the direction of this relationship. CONCLUSIONS: The findings are consistent with the view that high CR puts people at risk for recurrent depression and is less relevant for the development of an incidental depressive episode. This suggests that CR is an important target for interventions that aim to prevent the recurrence of depression.

Understanding emotion and emotional scarring in recurrent depression.

BACKGROUND: A single-item assessment of sad mood after remission from MDD is predictive of relapse, yet the mechanisms that play a role in depressive relapse remain poorly understood. METHODS: In 283 patients, remitted from recurrent depression (DSM-IV-TR criteria; HAM-D17 score ≤ 10), we examined emotional scarring, that is, whether the number of previous depressive episodes was associated with higher levels of sad mood as assessed with a 1-item Visual Analogue Mood Scale (VAMS). We then fitted a cross-sectional multivariate regression model to predict sad mood levels, including the Dysfunctional Attitude Scale Version-A, cognitive reactivity (Leiden Index of Depression Sensitivity), Ruminative Response Scale, and Everyday Problem Checklist. RESULTS: Patients with greater numbers of prior episodes experienced higher levels of sad mood after remission. In multivariate regression, intensity of daily stress and dysfunctional beliefs were associated with the VAMS (Adj. R(2)=.091) although not over and above depressive symptomatology (Adj. R(2)=.114). Cognitive reactivity was not associated with sadness. CONCLUSIONS: Our finding that patients with more previous MDEs reported higher levels of sad mood while remitted could be indicative of emotional scarring. Dysfunctional beliefs and intensity of daily stress were associated with sad mood but not over and above residual symptoms. Thus, illness related characteristics especially are associated with sad mood after remission. More negative affect after remission could result in lower stress tolerance or more stress intensity could result in negative affect. Future studies should examine premorbid sadness in a longitudinal cohort, and should study the exact pathway from stress, affect, and cognition to relapse.

Personality and cognitive vulnerability in remitted recurrently depressed patients.

INTRODUCTION: Personality disorders (PDs) have been associated with a poor prognosis of Major Depressive Disorder (MDD). The aim of the current study was to examine cognitive vulnerability (i.e., dysfunctional beliefs, extremity of beliefs, cognitive reactivity, and rumination) that might contribute to this poor prognosis of patients with PD comorbidity. METHODS: 309 outpatients with remitted recurrent MDD (SCID-I; HAM-D17 ≤ 10) were included within two comparable RCTs and were assessed at baseline with the Personality Diagnostic Questionnaire-4(+) (PDQ-4(+)), the Dysfunctional Attitude Scale Version-A (DAS-A), the Leiden Index of Depression Sensitivity (LEIDS), the Ruminative Response Scale (RRS), and the Inventory of Depressive Symptomatology-Self Report (IDS-SR). RESULTS: We found an indication that the PD prevalence was 49.5% in this remitted recurrently depressed sample. Having a PD (and higher levels of personality pathology) was associated with dysfunctional beliefs, cognitive reactivity, and rumination. Extreme 'black and white thinking' on the DAS was not associated with personality pathology. Brooding was only associated with a Cluster C classification (t(308) = 4.03, p < .001) and with avoidant PD specifically (t(308) = 4.82, p < .001), while surprisingly not with obsessive-compulsive PD. LIMITATIONS: PDs were assessed by questionnaire and the analyses were cross-sectional in nature. CONCLUSION: Being the first study to examine cognitive reactivity and rumination in patients with PD and remitted MDD, we demonstrated that even after controlling for depressive symptomatology, dysfunctional beliefs, cognitive reactivity, and rumination were associated with personality pathology. Rumination might be a pathway to relapse for patients with avoidant PD. Replication of our findings concerning cognitive vulnerability and specific PDs is necessary.

How do you feel? Detection of recurrent Major Depressive Disorder using a single-item screening tool.

Mood is a key element of Major Depressive Disorder (MDD), and is perceived as a highly dynamic construct. The aim of the current study was to examine whether a single-item mood scale can be used for mood monitoring. One hundred thirty remitted out-patients were assessed using the Structured Clinical Interview for DSM-IV Axis-I Disorders (SCID-I), Visual Analogue Mood Scale (VAMS), 17-item Hamilton Depression Rating Scale (HAM-D17), and Inventory of Depressive Symptomatology-Self Report (IDS-SR). Of all patients, 13.8% relapsed during follow-up assessments. Area under the curves (AUCs) for the VAMS, HAM-D17 and IDS-SR were 0.94, 0.91, and, 0.86, respectively. The VAMS had the highest positive predictive value (PPV) without any false negatives at score 55 (PPV=0.53; NPV=1.0) and was the best predictor of current relapse status (variance explained for VAMS: 60%; for HAM-D17: 49%; for IDS-SR: 34%). Only the HAM-D17 added significant variance to the model (7%). Assessing sad mood with a single-item mood scale seems to be a straightforward and patient-friendly avenue for life-long mood monitoring. Using a diagnostic interview (e.g., the SCID) in case of a positive screen is warranted. Repeated assessment of the VAMS using Ecological Momentary Assessment (EMA) might reduce false positives.

Mood reactivity rather than cognitive reactivity is predictive of depressive relapse: a randomized study with 5.5-year follow-up.

OBJECTIVE: The current study examined whether cognitive reactivity, cognitive extremity reactivity, and mood reactivity following mood provocation predicted relapse in depression over 5.5 years. Additionally, this study was the 1st to examine whether changes in cognitive reactivity and mood reactivity following preventive cognitive therapy (PCT) mediated the preventive effect of PCT on relapse. METHOD: One hundred eighty-seven remitted recurrently depressed outpatients were randomized over treatment as usual (TAU) versus TAU + PCT with 5.5-year follow-up. Relapse in depression was assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (Spitzer, Williams, Gibbon, & First, 1990). RESULTS: Mood reactivity predicted time to relapse over 5.5 years. We found no evidence that cognitive reactivity was a risk factor for relapse in depression. Moreover, unprimed dysfunctional beliefs predicted relapse directly. There was no indication of mediation by changes in cognitive reactivity (including extremity of the beliefs and unprimed beliefs) or mood reactivity on the preventive effect of PCT. Further, explorative analyses revealed that increases in cognitive and mood reactivity over time also predicted time to relapse. CONCLUSIONS: Our findings highlight a need to focus on mood reactivity instead of beliefs as a risk factor for relapse in depression. Similar to a previous study, we found no indications that cognitive therapy after remission reduced dysfunctional beliefs, cognitive reactivity, or extremity. Future studies should examine cognitive reactivity and mood reactivity in daily life as predictors of relapse.

Can a one-item mood scale do the trick? Predicting relapse over 5.5-years in recurrent depression.

BACKGROUND: To examine whether a simple Visual Analogue Mood Scale (VAMS) is able to predict time to relapse over 5.5-years. METHODOLOGY/PRINCIPAL FINDINGS: 187 remitted recurrently depressed out-patients were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the 17-item Hamilton Depression rating scale (HAM-D) to verify remission status (HAM-D <10). All patients rated their current mood with the help of a Visual Analogue Mood Scale (VAMS) at baseline and at a follow-up assessment three months later. Relapse over 5.5-years was assessed by the SCID-I. Cox regression revealed that both the VAMS at baseline and three months later significantly predicted time to relapse over 5.5-years. Baseline VAMS even predicted time to relapse when the number of previous depressive episodes and HAM-D scores were controlled for. The baseline VAMS explained 6.3% of variance in time to relapse, comparable to the HAM-D interview. CONCLUSIONS/SIGNIFICANCE: Sad mood after remission appears to play a pivotal role in the course of depression. Since a simple VAMS predicted time to relapse, the VAMS might be an easy and time-effective way to monitor mood and risk of early relapse, and offers possibilities for daily monitoring using e-mail and SMS. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Register Identifier: ISRCTN68246470.

Disrupting the rhythm of depression: design and protocol of a randomized controlled trial on preventing relapse using brief cognitive therapy with or without antidepressants.

BACKGROUND: Maintenance treatment with antidepressants is the leading strategy to prevent relapse and recurrence in patients with recurrent major depressive disorder (MDD) who have responded to acute treatment with antidepressants (AD). However, in clinical practice most patients (up to 70-80%) are not willing to take this medication after remission or take too low dosages. Moreover, as patients need to take medication for several years, it may not be the most cost-effective strategy. The best established effective and available alternative is brief cognitive therapy (CT). However, it is unclear whether brief CT while tapering antidepressants (AD) is an effective alternative for long term use of AD in recurrent depression. In addition, it is unclear whether the combination of AD to brief CT is beneficial. METHODS/DESIGN: Therefore, we will compare the effectiveness and cost-effectiveness of brief CT while tapering AD to maintenance AD and the combination of CT with maintenance AD. In addition, we examine whether the prophylactic effect of CT was due to CT tackling illness related risk factors for recurrence such as residual symptoms or to its efficacy to modify presumed vulnerability factors of recurrence (e.g. rigid explicit and/or implicit dysfunctional attitudes). This is a multicenter RCT comparing the above treatment scenarios. Remitted patients on AD with at least two previous depressive episodes in the past five years (n = 276) will be recruited. The primary outcome is time related proportion of depression relapse/recurrence during minimal 15 months using DSM-IV-R criteria as assessed by the Structural Clinical Interview for Depression. Secondary outcome: economic evaluation (using a societal perspective) and number, duration and severity of relapses/recurrences. DISCUSSION: This will be the first trial to investigate whether CT is effective in preventing relapse to depression in recurrent depression while tapering antidepressant treatment compared to antidepressant treatment alone and the combination of both. In addition, we explore explicit and implicit mediators of CT. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1907.