Development of an implementation plan for a school-based multimodal approach for depression and suicide prevention in adolescents.

Strong Teens and Resilient Minds (STORM) is a multimodal, school-based approach for depression and suicide prevention in adolescents that is currently implemented in a region in the Netherlands. The STORM approach will be implemented in new regions in the coming years. This study used the implementation mapping protocol to report on the development of the STORM implementation plan. First, a needs assessment was conducted through semi-structured interviews with stakeholders and brainstorming sessions with regional programme leaders in the two regions that started implementing STORM in 2023. This led to the identification of six main barriers to implementation: high level of demands for schools, insufficient understanding of the programme content, insufficient network collaboration, no perceived relative advantage of STORM by stakeholders, lack of attention to sustainability, and high work pressure. Second, performance and change objectives were formulated based on these barriers. For example, a performance objective for potential providers was that they felt supported by STORM. Third, implementation strategies were selected from theory and translated into practical applications through brainstorming sessions with programme leaders. The following strategies were included in the implementation plan: collaborate with similar initiatives within the region, free up time for STORM tasks, tailor strategies, identify and prepare STORM champions, and promote network weaving. Last, a plan to evaluate the implementation of STORM and the application of the STORM implementation plan was formulated. Planned evaluation research will provide more insight into the usefulness and impact of the STORM implementation plan.

Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension.

About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.

Cost-effectiveness of behavioral activation compared to treatment as usual for depressed older adults in primary care: A cluster randomized controlled trial.

INTRODUCTION: Depression in older adults is associated with decreased quality of life and increased utilization of healthcare services. Behavioral activation (BA) is an effective treatment for late-life depression, but the cost-effectiveness compared to treatment as usual (TAU) is unknown. METHODS: An economic evaluation was performed alongside a cluster randomized controlled multicenter trial including 161 older adults (≥65 years) with moderate to severe depressive symptoms (PHQ-9 ≥ 10). Outcome measures were depression (response on the QIDS-SR), quality-adjusted life-years (QALYs) and societal costs. Missing data were imputed using multiple imputation. Cost and effect differences were estimated using bivariate linear regression models, and statistical uncertainty was estimated with bootstrapping. Cost-effectiveness acceptability curves showed the probability of cost-effectiveness at different ceiling ratios. RESULTS: Societal costs were statistically non-significantly lower in BA compared to TAU (mean difference (MD) -€485, 95 % CI -3861 to 2792). There were no significant differences in response on the QIDS-SR (MD 0.085, 95 % CI -0.015 to 0.19), and QALYs (MD 0.026, 95 % CI -0.0037 to 0.055). On average, BA was dominant over TAU (i.e., more effective and less expensive), although the probability of dominance was only 0.60 from the societal perspective and 0.85 from the health care perspective for both QIDS-SR response and QALYs. DISCUSSION: Although the results suggest that BA is dominant over TAU, there was considerable uncertainty surrounding the cost-effectiveness estimates which precludes firm conclusions.

Long-term outcomes of once weekly v. twice weekly sessions of cognitive behavioral therapy and interpersonal psychotherapy for depression.

BACKGROUND: Twice weekly sessions of cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT) for major depressive disorder (MDD) lead to less drop-out and quicker and better response compared to once weekly sessions at posttreatment, but it is unclear whether these effects hold over the long run. AIMS: Compare the effects of twice weekly v. weekly sessions of CBT and IPT for depression up to 24 months since the start of treatment. METHODS: Using a 2 × 2 factorial design, this multicentre study randomized 200 adults with MDD to once or twice weekly sessions of CBT or IPT over 16-24 weeks, up to a maximum of 20 sessions. Main outcome measures were depression severity, measured with the Beck Depression Inventory-II and the Longitudinal Interval Follow-up Evaluation. Intention-to-treat analyses were conducted. RESULTS: Compared with patients who received once weekly sessions, patients who received twice weekly sessions showed a significant decrease in depressive symptoms up through month 9, but this effect was no longer apparent at month 24. Patients who received CBT showed a significantly larger decrease in depressive symptoms up to month 24 compared to patients who received IPT, but the between-group effect size at month 24 was small. No differential effects between session frequencies or treatment modalities were found in response or relapse rates. CONCLUSIONS: Although a higher session frequency leads to better outcomes in the acute phase of treatment, the difference in depression severity dissipated over time and there was no significant difference in relapse.

Cost-effectiveness of twice-weekly versus once-weekly sessions of cognitive-behavioural therapy and interpersonal psychotherapy for depression at 12 months after start of treatment: randomised controlled trial.

BACKGROUND: Cost-effective treatments are needed to reduce the burden of depression. One way to improve the cost-effectiveness of psychotherapy might be to increase session frequency, but keep the total number of sessions constant. AIM: To evaluate the cost-effectiveness of twice-weekly compared with once-weekly psychotherapy sessions after 12 months, from a societal perspective. METHOD: An economic evaluation was conducted alongside a randomised controlled trial comparing twice-weekly versus once-weekly sessions of psychotherapy (cognitive-behavioural therapy or interpersonal psychotherapy) for depression. Missing data were handled by multiple imputation. Statistical uncertainty was estimated with bootstrapping and presented with cost-effectiveness acceptability curves. RESULTS: Differences between the two groups in depressive symptoms, physical and social functioning, and quality-adjusted life-years (QALY) at 12-month follow-up were small and not statistically significant. Total societal costs in the twice-weekly session group were higher, albeit not statistically significantly so, than in the once-weekly session group (mean difference €2065, 95% CI -686 to 5146). The probability that twice-weekly sessions are cost-effective compared with once-weekly sessions was 0.40 at a ceiling ratio of €1000 per point improvement in Beck Depression Inventory-II score, 0.32 at a ceiling ratio of €50 000 per QALY gained, 0.23 at a ceiling ratio of €1000 per point improvement in physical functioning score and 0.62 at a ceiling ratio of €1000 per point improvement in social functioning score. CONCLUSIONS: Based on the current results, twice-weekly sessions of psychotherapy for depression are not cost-effective over the long term compared with once-weekly sessions.

Supporting antidepressant discontinuation using mindfulness plus monitoring versus monitoring alone: A cluster randomized trial in general practice.

Discontinuing antidepressant medication (ADM) can be challenging for patients and clinicians. In the current study we investigated if Mindfulness-Based Cognitive Therapy (MBCT) added to supported protocolized discontinuation (SPD) is more effective than SPD alone to help patients discontinue ADM. This study describes a prospective, cluster-randomized controlled trial (completed). From 151 invited primary care practices in the Netherlands, 36 (24%) were willing to participate and randomly allocated to SPD+MBCT (k = 20) or SPD (k = 16). Adults using ADM > 9 months were invited by GPs to discuss tapering, followed by either MBCT+SPD, or SPD alone. Exclusion criteria included current psychiatric treatment; substance use disorder; non-psychiatric indication for ADM; attended MBCT within past 5 years; cognitive barriers. From the approximately 3000 invited patients, 276 responded, 119 participated in the interventions and 92 completed all assessments. All patients were offered a decision aid and a personalized tapering schedule (with GP). MBCT consisted of eight group sessions of 2.5 hours and one full day of practice. SPD was optional and consisted of consultations with a mental health assistant. Patients were assessed at baseline and 6, 9 and 12 months follow-up, non-blinded. In line with our protocol, primary outcome was full discontinuation of ADM within 6 months. Secondary outcomes were depression, anxiety, withdrawal symptoms, rumination, well-being, mindfulness skills, and self-compassion. Patients allocated to SPD + MBCT (n = 73) were not significantly more successful in discontinuing (44%) than those allocated to SPD (n = 46; 33%), OR 1.60, 95% CI 0.73 to 3.49, p = .24, number needed to treat = 9. Only 20/73 allocated to MBCT (27%) completed MBCT. No serious adverse events were reported. In conclusion, we were unable to demonstrate a significant benefit of adding MBCT to SPD to support discontinuation in general practice. Actual participation in patient-tailored interventions was low, both for practices and for patients. (Trial registration: ClinicalTrials.gov PRS ID: NCT03361514 registered December 2017).

Behavioural Activation versus Treatment as Usual for Depressed Older Adults in Primary Care: A Pragmatic Cluster-Randomised Controlled Trial.

INTRODUCTION: Effective non-pharmacological treatment options for depression in older adults are lacking. OBJECTIVE: The effectiveness of behavioural activation (BA) by mental health nurses (MHNs) for depressed older adults in primary care compared with treatment as usual (TAU) was evaluated. METHODS: In this multicentre cluster-randomised controlled trial, 59 primary care centres (PCCs) were randomised to BA and TAU. Consenting older (≥65 years) adults (n = 161) with clinically relevant symptoms of depression (PHQ-9 ≥ 10) participated. Interventions were an 8-week individual MHN-led BA programme and unrestricted TAU in which general practitioners followed national guidelines. The primary outcome was self-reported depression (QIDS-SR16) at 9 weeks and 3, 6, 9, and 12-month follow-up. RESULTS: Data of 96 participants from 21 PCCs in BA and 65 participants from 16 PCCs in TAU, recruited between July 4, 2016, and September 21, 2020, were included in the intention-to-treat analyses. At post-treatment, BA participants reported significantly lower severity of depressive symptoms than TAU participants (QIDS-SR16 difference = -2.77, 95% CI = -4.19 to -1.35), p < 0.001; between-group effect size = 0.90; 95% CI = 0.42-1.38). This difference persisted up to the 3-month follow-up (QIDS-SR16 difference = -1.53, 95% CI = -2.81 to -0.26, p = 0.02; between-group effect size = 0.50; 95% CI = 0.07-0.92) but not up to the 12-month follow-up [QIDS-SR16 difference = -0.89 (-2.49 to 0.71)], p = 0.28; between-group effect size = 0.29 (95% CI = -0.82 to 0.24). CONCLUSIONS: BA led to a greater symptom reduction of depressive symptoms in older adults, compared to TAU in primary care, at post-treatment and 3-month follow-up, but not at 6- to 12-month follow-up.

Follow-up outcomes of Mindfulness-Based Cognitive Therapy (MBCT) for patients with chronic, treatment-resistant depression.

BACKGROUND: Mindfulness-based cognitive therapy (MBCT) is an evidence-based treatment for depression. The current study focused on the long-term outcomes of MBCT for chronically, treatment-resistant depressed patients during a 6-months follow-up period. Additionally, predictors of treatment outcomes were explored. METHOD: The outcomes of MBCT on depressive symptoms, remission rates, quality of life, rumination, mindfulness skills and self-compassion were investigated in a cohort of chronically, treatment-resistant depressed outpatients (N = 106), who had taken part in an RCT comparing MBCT with treatment-as-usual (TAU). Measures were assessed pre-MBCT, post-MBCT, at 3-months follow-up, and at 6-months follow-up. RESULTS: Results of linear mixed effect models and Bayesian repeated measures ANOVA's reveal that depressive symptoms, quality of life, rumination, mindfulness skills and self-compassion consolidated during follow-up. Remission rates even further increased over the course of follow-up. When controlling for symptoms at baseline, higher baseline levels of rumination predicted lower depressive symptoms and quality of life at 6-month follow-up. No other predictors (i.e. duration of current depressive episode, level of treatment-resistance, childhood trauma, mindfulness skills, self-compassion) were found. LIMITATIONS: All participants received MBCT, therefore time or other non-specific effects might have influenced the results and replication studies including a control conditions are needed. CONCLUSIONS: Results indicate that the clinical benefits of MBCT for chronically, treatment-resistant depressed patients persist up to 6 months after completing MBCT. Duration of the current episode, level of treatment-resistance, childhood trauma and baseline levels of mindfulness skills and self-compassion did not predict treatment outcome. When controlling for baseline depressive symptoms participants with high levels of rumination seem to benefit more; however more research is needed. TRIAL REGISTRY: Dutch Trial Registry, number NTR4843.

Closing the gap between screening and depression prevention: a qualitative study on barriers and facilitators from the perspective of public health professionals in a school-based prevention approach.

BACKGROUND: The prevalence of depression has increased among adolescents in western countries. Prevention is needed to reduce the number of adolescents who experience depression and to avoid negative consequences, including suicide. Several preventive interventions are found to be promising, especially multi-modal approaches, for example combining screening and preventive intervention. However, an important bottleneck arises during the implementation of preventive intervention. Only a small percentage of adolescents who are eligible for participation actually participate in the intervention. To ensure that more adolescents can benefit from prevention, we need to close the gap between detection and preventive intervention. We investigated the barriers and facilitators from the perspective of public health professionals in screening for depressive and suicidal symptoms and depression prevention referral in a school-based setting. METHODS: We conducted 13 semi-structured interviews with public health professionals, who execute screening and depression prevention referral within the Strong Teens and Resilient Minds (STORM) approach. The interviews were recorded, transcribed verbatim, and coded in several cycles using ATLAS.ti Web. RESULTS: Three main themes of barriers and facilitators emerged from the interviews, namely "professional capabilities," "organization and collaboration," and "beliefs about depressive and suicidal symptoms and participation in prevention". The interviews revealed that professionals do not always feel sufficiently equipped in terms of knowledge, skills and supporting networks. Consequently, they do not always feel well able to execute the process of screening and prevention referral. In addition, a lack of knowledge and support in schools and other cooperating organizationorganizations was seen to hinder the process. Last, the beliefs of public health professionals, school staff, adolescents, and parents -especially stigma and taboo-were found to make the screening and prevention referral process more challenging. CONCLUSIONS: To further improve the process of screening and prevention referral in a school-based setting, enhancing professional competence and a holding work environment for professionals, a strong collaboration and a joint approach with schools and other cooperating organizations and society wide education about depressive and suicidal symptoms and preventive intervention are suggested. Future research should determine whether these recommendations actually lead to closing the gap between detection and prevention.

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Evidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects. Objective: To determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD). Design, Setting, and Participants: This randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications. Intervention: In the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage. Main Outcomes and Measures: The primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores). Results: Of 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT. Conclusions and Relevance: In this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03548675.

Second Opinions for Patients With a Persistent Depressive Disorder: Effects on Severity of Depression and Quality of Life.

BACKGROUND: A persistent depressive disorder has a major impact on both patients and health care systems. Despite the advice in guidelines to seek a second opinion if there is insufficient evidence of recovery after treatment, and the great number of second opinions in psychiatric care for patients with persistent depression, only a few studies have been published about their effects. METHODS: Multilevel analyses were conducted to compare the mean test scores of a group of patients with a persistent depressive disorder who received the intervention of a second opinion with scores from a matched control group, at 3 time points: baseline, intervention, and follow-up. RESULTS: A significant decrease in the severity of depression 3 months after the second opinion was found. No effects on quality of life or treatment satisfaction were found. LIMITATIONS: The study sample was a convenience sample without randomization, and many values were missing in the data. In addition, a 3-month follow-up may have been too short to expect effects of the recommendations from the second opinion. The instructions concerning how to rate treatment satisfaction were also ambiguous. CONCLUSIONS: A second opinion can be of value for persistent depression. Further research should address the question of whether the effect that was found is caused by the second opinion itself or is the result of subsequent changes in treatment.

Efficacy and moderators of short-term psychodynamic psychotherapy for depression: A systematic review and meta-analysis of individual participant data.

BACKGROUND: Short-term psychodynamic psychotherapy (STPP) is frequently used to treat depression, but it is unclear which patients might benefit specifically. Individual participant data (IPD) meta-analyses can provide more precise effect estimates than conventional meta-analyses and identify patient-level moderators. This IPD meta-analysis examined the efficacy and moderators of STPP for depression compared to control conditions. METHODS: PubMed, PsycInfo, Embase, and Cochrane Library were searched September 1st, 2022, to identify randomized trials comparing STPP to control conditions for adults with depression. IPD were requested and analyzed using mixed-effects models. RESULTS: IPD were obtained from 11 of the 13 (84.6%) studies identified (n = 771/837, 92.1%; mean age = 40.8, SD = 13.3; 79.3% female). STPP resulted in significantly lower depressive symptom levels than control conditions at post-treatment (d = -0.62, 95%CI [-0.76, -0.47], p < .001). At post-treatment, STPP was more efficacious for participants with longer rather than shorter current depressive episode durations. CONCLUSIONS: These results support the evidence base of STPP for depression and indicate episode duration as an effect modifier. This moderator finding, however, is observational and requires prospective validation in future large-scale trials.

Working it out: can an acute exercise bout alleviate memory bias, rumination and negative mood?

Although it is well known that exercise reduces depressive symptoms, the underlying psychological mechanisms remain unclear. This experimental study examined the acute effect of exercise on mood, and depressotypic memory bias and state rumination. Trait rumination was tested as a possible moderator. A sample of non-regular exercisers (N = 100) was randomized to exercise or rest. After a negative mood induction, the exercise condition cycled for 24 min at moderate intensity, while the rest condition rested. Negative and overgeneral memory bias, as well as positive and negative affect were assessed after exercise/rest. To capture the lingering of negative mood and state rumination, both were assessed multiple times throughout the study. The exercise (as compared to rest) condition reported more positive affect. However, no differences were found on overgeneral memory bias, as well as depression-specific mood or state rumination measured throughout the study. Interestingly, the exercise condition showed more negative memory bias at higher levels of rumination. Individual differences in trait rumination moderated the exercise-memory bias relation, such that exercise increased negative memory bias at higher levels of rumination. It is possible that long-term exercise protocols are necessary to change cognitive processes related to depression.

The effectiveness of peer support for individuals with mental illness: systematic review and meta-analysis.

BACKGROUND: The benefits of peer support interventions (PSIs) for individuals with mental illness are not well known. The aim of this systematic review and meta-analysis was to assess the effectiveness of PSIs for individuals with mental illness for clinical, personal, and functional recovery outcomes. METHODS: Searches were conducted in PubMed, Embase, and PsycINFO (December 18, 2020). Included were randomized controlled trials (RCTs) comparing peer-delivered PSIs to control conditions. The quality of records was assessed using the Cochrane Collaboration Risk of Bias tool. Data were pooled for each outcome, using random-effects models. RESULTS: After screening 3455 records, 30 RCTs were included in the systematic review and 28 were meta-analyzed (4152 individuals). Compared to control conditions, peer support was associated with small but significant post-test effect sizes for clinical recovery, g = 0.19, 95% CI (0.11-0.27), I2 = 10%, 95% CI (0-44), and personal recovery, g = 0.15, 95% CI (0.04-0.27), I2 = 43%, 95% CI (1-67), but not for functional recovery, g = 0.08, 95% CI (-0.02 to 0.18), I2 = 36%, 95% CI (0-61). Our findings should be considered with caution due to the modest quality of the included studies. CONCLUSIONS: PSIs may be effective for the clinical and personal recovery of mental illness. Effects are modest, though consistent, suggesting potential efficacy for PSI across a wide range of mental disorders and intervention types.

User Engagement Within an Online Peer Support Community (Depression Connect) and Recovery-Related Changes in Empowerment: Longitudinal User Survey.

BACKGROUND: The chronic nature of depression and limited availability of evidence-based treatments emphasize the need for complementary recovery-oriented services, such as peer support interventions (PSIs). Peer support is associated with positive effects on clinical and personal recovery from mental illness, but little is known about the processes of engagement that foster change, and studies targeting individuals with depression specifically are limited. OBJECTIVE: This study aimed to evaluate whether the level of user engagement, assessed on several dimensions, in an online peer support community for individuals with depression promotes empowerment and the use of self-management strategies and reduces symptom severity and disability. METHODS: In a longitudinal survey conducted from June 2019 to September 2020, we analyzed the data of the users of Depression Connect (DC), an online peer support community hosted by the Dutch Patient Association for Depression and the Pro Persona Mental Health Care institute, on measures of empowerment, self-management, depression, and disability. Of the 301 respondents, 49 (16.3%) respondents completed the survey again after 3 months and 74 (24.6%) respondents, after 6 months. Analysis of 3 parameters (ie, total time spent on the platform, number of page views, and number of posts) derived from their data logs yielded 4 engagement profiles. Linear mixed models were fitted to determine whether the outcomes had significantly changed over time and differed for the various profiles. RESULTS: Baseline engagement with the online peer support community was "very low" (177/301, 58.8%) or "low" (87/301, 28.9%) for most of the participants, with few showing "medium" (30/301, 9.9%) or "high" engagement patterns (7/301, 2.3%), while user profiles did not differ in demographic and clinical characteristics. Empowerment, self-management, depressive symptoms, and disability improved over time, but none were associated with the intensity or nature of user engagement. CONCLUSIONS: With most DC members showing very low to low engagement and only a few being identified as high-engaged users, it is likely that this flexibility in use frequency is what provides value to online PSI users. In other more formal supportive environments for depression, a certain level of engagement is predetermined either by their organizational or by their societal context; at DC, users can adapt the intensity and nature of their engagement to their current needs on their personal road to recovery. This study added to the current knowledge base on user engagement for PSIs because previous studies targeting depression with an online format focused on active users, precluding passive and flexible engagement. Future studies should explore the content and quality of the interactions in online PSIs to identify optimal user engagement as a function of current, self-reported clinical parameters and reasons to engage in the PSI.

Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability.

Ketamine has rapid yet often transient antidepressant effects in patients with treatment-resistant depression. Different strategies have been proposed to prolong these effects. Maintenance ketamine treatment appears promising, but little is known about its efficacy, safety, and tolerability in depression. We searched Pubmed, Embase, and the Cochrane Library and identified three randomised controlled trials, eight open-label trials, and 30 case series and reports on maintenance ketamine treatment. We found intravenous, intranasal, oral, and possibly intramuscular and subcutaneous maintenance ketamine treatment to be effective in sustaining antidepressant effect in treatment-resistant depression. Tachyphylaxis, cognitive impairment, addiction, and serious renal and urinary problems seem uncommon. Despite the methodological limitations, we conclude that from a clinical view, maintenance ketamine treatment seems to be of therapeutic potential. We recommend both controlled and naturalistic studies with long-term follow-up and sufficient power to determine the position of maintenance ketamine treatment within routine clinical practice.

The association between sample and treatment characteristics and the efficacy of repetitive transcranial magnetic stimulation in depression: A meta-analysis and meta-regression of sham-controlled trials.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neuromodulation that is increasingly used to treat major depressive disorder (MDD). However, treatment with rTMS could be optimized by identifying optimal treatment parameters or characteristics of patients that are most likely to benefit. This meta-analysis and meta-regression aims to identify sample and treatment characteristics that are associated with change in depressive symptom level, treatment response and remission. METHODS: The databases PubMed, Embase, Web of Science and Cochrane library were searched for randomized controlled trials (RCTs) reporting on the therapeutic efficacy of high-frequent, low-frequent, or bilateral rTMS for MDD compared to sham. Study and sample characteristics as well as rTMS parameters and outcome variables were extracted. Effect sizes were calculated for change in depression score and risk ratios for response and remission. RESULTS: Sixty-five RCTs with a total of 2982 subjects were included in this meta-analysis. Active rTMS resulted in a larger depressive symptom reduction than sham protocol (Hedges' g = -0.791 95% CI -0.977; -0.605). Risk ratios for response and remission were 2.378 (95% CI 1.882; 3.005) and 2.450 (95% CI 1.779; 3.375), respectively. We found no significant association between sample and treatment parameters and rTMS efficacy. CONCLUSIONS: rTMS is an efficacious treatment for MDD. No associations between sample or treatment characteristics and efficacy were found, for which we caution that publication bias, heterogeneity and lack of consistency in the definition of remission might bias these latter null findings. Our results are clinically relevant and support the use of rTMS as a non-invasive and effective treatment option for depression.

The effect of mindfulness-based cognitive therapy on rumination and a task-based measure of intrusive thoughts in patients with bipolar disorder.

BACKGROUND: Preliminary evidence suggests that Mindfulness-Based Cognitive Therapy (MBCT) is a promising treatment for bipolar disorder (BD). A proposed working mechanism of MBCT in attenuating depressive symptoms is reducing depressive rumination. The primary aim of this study was to investigate the effect of MBCT on self-reported trait depressive rumination and an experimental state measure of negative intrusive thoughts in BD patients. Exploratively, we investigated the effect of MBCT on positive rumination and positive intrusive thoughts. METHODS: The study population consisted of a subsample of bipolar type I or II patients participating in a multicenter randomized controlled trial comparing MBCT + treatment as usual (TAU) (N = 25) to TAU alone (N = 24). Trait depressive rumination (RRS brooding subscale) and intrusive thoughts (breathing focus task (BFT)) were assessed at baseline (full subsample) and post-treatment (MBCT + TAU; n = 15, TAU; n = 15). During the BFT, participants were asked to report negative, positive and neutral intrusive thoughts while focusing on their breathing. RESULTS: Compared to TAU alone, MBCT + TAU resulted in a significant pre- to post-treatment reduction of trait depressive rumination (R2 = .16, F(1, 27) = 5.15, p = 0.031; medium effect size (f2 = 0.19)) and negative intrusive thoughts on the BFT (R2 = .15, F(1, 28) = 4.88, p = 0.036; medium effect size (f2 = 0.17)). MBCT did not significantly change positive rumination or positive intrusive thoughts. CONCLUSIONS: MBCT might be a helpful additional intervention to reduce depressive rumination in BD which might reduce risk of depressive relapse or recurrence. Considering the preliminary nature of our findings, future research should replicate our findings and explore whether this reduction in rumination following MBCT indeed mediates a reduction in depressive symptoms and relapse or recurrence in BD.

rTMS combined with CBT as a next step in antidepressant non-responders: a study protocol for a randomized comparison with current antidepressant treatment approaches.

BACKGROUND: Major depressive disorder (MDD) is one of the most common psychiatric disorders, however, current treatment options are insufficiently effective for about 35% of patients, resulting in treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neuromodulation that is effective in treating TRD. Not much is known about the comparative efficacy of rTMS and other treatments and their timing within the treatment algorithm, making it difficult for the treating physician to establish when rTMS is best offered as a treatment option. This study aims to investigate the (cost-)effectiveness of rTMS (in combination with cognitive behavioral therapy (CBT) and continued antidepressant medication), compared to the next step in the treatment algorithm. This will be done in a sample of patients with treatment resistant non-psychotic unipolar depression. METHODS: In this pragmatic multicenter randomized controlled trial 132 patients with MDD are randomized to either rTMS or the next pharmacological step within the current treatment protocol (a switch to a tricyclic antidepressant or augmentation with lithium or a second-generation antipsychotic). Both groups also receive CBT. The trial consists of 8 weeks of unblinded treatment followed by follow-up of the cohort at four and 6 months. A subgroup of patients (n = 92) will have an extended follow-up at nine and 12 months to assess effect decay or retention. We expect that rTMS is more (cost-)effective than medication in reducing depressive symptoms in patients with TRD. We will also explore the effects of both treatments on symptoms associated with depression, e.g. anhedonia and rumination, as well as the effect of expectations regarding the treatments on its effectiveness. DISCUSSION: The present trial aims to inform clinical decision making about whether rTMS should be considered as a treatment option in patients with TRD. The results may improve treatment outcomes in patients with TRD and may facilitate adoption of rTMS in the treatment algorithm for depression and its implementation in clinical practice. TRIAL REGISTRATION: This trial is registered within the Netherlands Trial Register (code: NL7628 , date: March 29th 2019).

A piece of the puzzle: Does bipolarity partly explain the high prevalence of treatment resistance in depression?

In this cross-sectional study we examined whether the prevalence of treatment resistant depression (TRD) can be partly attributed to level of bipolarity. We included data of 201 patients with either episodic depression or TRD, who received treatment for their depression at either an outpatient or 2nd opinion/daytime setting, within a specialised mental healthcare department in the Netherlands. Whether level of TRD, assessed by the 'Dutch Measure for quantification of Treatment Resistance in Depression', can be partly explained by level of bipolarity, assessed by 'the Bipolarity Index', was examined using linear regression. We found no direct association between level of TRD and level of bipolarity, nor did comorbid anxiety disorders obscure an existing association. In this study we found no evidence for overlooked bipolarity contributing to the high prevalence of TRD. If replicated, we could state that additional screening on bipolarity with an instrument such as the 'Bipolarity Index' in the specialised mental health care is unnecessary.