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Abstract Background Despite the availability of a wide variety of evidence-based treatments for major depressive disorder (MDD), many patients still experience impairments in their lives after remission. Programs are needed that effectively support patients in coping with these impairments. The program Storytelling and Training to Advance Individual Recovery Skills (STAIRS) was developed to address this need and combines the use of peer contact, expert-by-experience guidance, family support and professional blended care. The aim of the planned study is (1) to assess the efficacy of the STAIRS program in patients with remitted MDD, (2) to investigate patients’ subjective experiences with STAIRS, and (3) to evaluate the program’s cost-effectiveness. Methods A concurrent mixed-methods randomized controlled trial design will be used. Patients aged between 18 and 65 years with remitted MDD (N = 140) will be randomized to either a group receiving care as usual (CAU) + the STAIRS-program or a control group receiving CAU + some basic psychoeducation. Quantitative efficacy data on functional and personal recovery and associated aspects will be collected using self-report questionnaires at the start of the intervention, immediately following the intervention, and at the six-month follow-up. Insights into patients’ experiences on perceived effects and the way in which different program elements contribute to this effect, as well as the usability and acceptability of the program, will be gained by conducting qualitative interviews with patients from the experimental group, who are selected using maximum variation sampling. Finally, data on healthcare resource use, productivity loss and quality of life will be collected and analysed to assess the cost-effectiveness and cost-utility of the STAIRS-program. Discussion Well-designed recovery-oriented programs for patients suffering from MDD are scarce. If efficacy and cost-effectiveness are demonstrated with this study and patients experience the STAIRS program as usable and acceptable, this program can be a valuable addition to CAU. The qualitative interviews may give insights into what works for whom, which can be used to promote implementation. Trial registration This trial was registered at ClinicalTrials.gov on 1 July 2021, registration number NCT05440812.

Abstract Background Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

Abstract Background Little is known about the public stigma on mental illness and mental health knowledge (MHK) in China, public stigma and low MHK can negatively affect patients’ health and increase the burden of mental disorders on society. This study aimed at investigating the rates of stigma and MHK, the correlates of stigma and MHK, and the association between MHK and stigma among a Chinese population. Methods The data is from the Tianjin Mental Health Survey (TJMHS), which involved a large and a representative sample of adult community residents in the Chinese municipality of Tianjin (n = 11,748). In a 12% random subsample (n = 1775) the Perceived Discrimination and Devaluation scale (PDD) and a Mental Health Knowledge Questionnaire (MHKQ) were administered. First, percentages of the responses to the individual items of the PDD and MHKQ were investigated. Second, sociodemographic correlates of PDD and MHK, and the association between stigma and MHK were investigated. Results We found that a sizable proportion of participants responded that others would hold a negative attitude towards (former) mental patients, especially with regard to engaging in closer personal relationships. Most people were not familiar about the causes, treatments and prevention of mental illness. Resident area, age, education level, Per capita family income and employment status were related to devaluation score and MHKQ score. MHK was negatively associated with public stigma. Conclusions There is room for improvement with regard to levels of public stigma and MHK in China. Providing psychoeducation to improve public MHK could also contribute to reduction of public stigma.

Abstract Background The past decades of research have seen an increase in statistical tools to explore the complex dynamics of mental health from patient data, yet the application of these tools in clinical practice remains uncommon. This is surprising, given that clinical reasoning, e.g., case conceptualizations, largely coincides with the dynamical system approach. We argue that the gap between statistical tools and clinical practice can partly be explained by the fact that current estimation techniques disregard theoretical and practical considerations relevant to psychotherapy. To address this issue, we propose that case conceptualizations should be formalized. We illustrate this approach by introducing a computational model of functional analysis, a framework commonly used by practitioners to formulate case conceptualizations and design patient-tailored treatment. Methods We outline the general approach of formalizing idiographic theories, drawing on the example of a functional analysis for a patient suffering from panic disorder. We specified the system using a series of differential equations and simulated different scenarios; first, we simulated data without intervening in the system to examine the effects of avoidant coping on the development of panic symptomatic. Second, we formalized two interventions commonly used in cognitive behavioral therapy (CBT; exposure and cognitive reappraisal) and subsequently simulated their effects on the system. Results The first simulation showed that the specified system could recover several aspects of the phenomenon (panic disorder), however, also showed some incongruency with the nature of panic attacks (e.g., rapid decreases were not observed). The second simulation study illustrated differential effects of CBT interventions for this patient. All tested interventions could decrease panic levels in the system. Conclusions Formalizing idiographic theories is promising in bridging the gap between complexity science and clinical practice and can help foster more rigorous scientific practices in psychotherapy, through enhancing theory development. More precise case conceptualizations could potentially improve intervention planning and treatment outcomes. We discuss applications in psychotherapy and future directions, amongst others barriers for systematic theory evaluation and extending the framework to incorporate interactions between individual systems, relevant for modeling social learning processes. With this report, we hope to stimulate future efforts in formalizing clinical frameworks.

Abstract Background Failure to seek treatment for mental health disorders is a serious public health concern. Unfortunately, there is little insight into help-seeking and its associated factors in China which has undergone rapid economic development in the past 30 years and has an increasing prevalence of mental disorder. Therefore, this study aimed to (1) investigate help-seeking rates in healthcare and non-healthcare settings and (2) investigate the correlates of help-seeking behavior in a large Chinese survey. Methods Data came from the Tianjin Mental Health Survey (TJMHS), a representative sample of adult community residents in the Chinese municipality of Tianjin (n = 11,748). Of these, 1759 individuals had ≥1 axis-I diagnosis according to the Diagnostic and Statistical manual– fourth edition (DSM-IV) and were administered a Help-Seeking Questionnaire. Results 15.7% of patients reported that they had ever sought help during their entire lifetime before the interview, with 4.5% seeking help in mental healthcare, 3.2% in other healthcare and 8.1% in non-healthcare settings (e.g., family, friends, and spiritual advisor). Among help-seekers, the first help was mostly sought in non-healthcare settings (58.4%), followed by healthcare (27.5%) and mental healthcare settings (24.5%). Female gender, younger age, having 7–9 years vs 0–6 years of education, a low income, a psychotic disorder and having ≥2 disorders were associated with increased help-seeking. Older age, being married and having a psychotic or organic disorder were associated with increased help-seeking in healthcare vs. non-healthcare settings. Conclusion A small percentage of persons with mental disorders in the Tianjin region seek help and among those who do, variations in the types of help-seeking may be partially explained by demographic and clinical characteristics.

Abstract Background There is an urgent need to develop additional treatment strategies for patients with treatment-resistant depression (TRD). The rapid but short-lived antidepressant effects of intravenous (IV) ketamine as a racemic mixture have been shown repeatedly in this population, but there is still a paucity of data on the efficacy and safety of (a) different routes of administration, and (b) ketamine’s enantiomers esketamine and arketamine. Given practical advantages of oral over IV administration and pharmacodynamic arguments for better antidepressant efficacy of esketamine over arketamine, we designed a study to investigate repeated administration of oral esketamine in patients with TRD. Methods This study features a triple-blind randomized placebo-controlled trial (RCT) comparing daily oral esketamine versus placebo as add-on to regular antidepressant medications for a period of 6 weeks, succeeded by a follow-up of 4 weeks. The methods support examination of the efficacy, safety, tolerability, mechanisms of action, and economic impact of oral esketamine in patients with TRD. Discussion This is the first RCT investigating repeated oral esketamine administration in patients with TRD. If shown to be effective and tolerated, oral esketamine administration poses important advantages over IV administration. Trial registration Dutch Trial Register, NTR6161. Registered 21 October 2016.

Abstract Background Unhealthy lifestyle behaviours contribute to alarming cardiometabolic risk in patients with serious mental illness (SMI). Evidence-based practical lifestyle tools supporting patients and staff in improving patient lifestyle are lacking. Methods This multi-site randomized controlled pragmatic trial determined the effectiveness of a twelve-month multimodal lifestyle approach, including a web-based tool to improve patients’ cardiometabolic health, versus care-as-usual. Using the web tool, nurses (trained in motivational interviewing) assisted patients in assessing their lifestyle behaviours, creating a risk profile and constructing lifestyle goals, which were discussed during fortnightly regular care visits. Twenty-seven community-care and sheltered-living teams were randomized into intervention (N = 17) or control (N = 10) groups, including 244 patients (140 intervention/104 control, 49.2% male, 46.1 ± 10.8 years) with increased waist circumference (WC), BMI or fasting glucose. The primary outcomes concerned differences in WC after six and twelve months intervention, while BMI and metabolic syndrome Z-score were secondary outcome measures. Results General multilevel linear mixed models adjusted for antipsychotic medication showed that differences in WC change between intervention and control were − 0.15 cm (95%CI: − 2.49; 2.19) after six and − 1.03 cm (95%CI: − 3.42; 1.35) after twelve months intervention; however, the differences were not statistically significant. No intervention effects were found for secondary outcome measures. The intervention increased patients’ readiness to change dietary behaviour. Conclusion A multimodal web-based intervention facilitating nurses to address lifestyle changes in SMI patients did not improve patient cardiometabolic health. Web-tool use was lower than expected and nurses need more lifestyle coaching knowledge and skills. The type of intervention and delivery mode need optimization to realize effective lifestyle care for SMI patients. Trial registration Dutch Trial Registry, www.trialregister.nl, NTR3765, 21 December 2012.

Abstract Background Affective disorders, encompassing depressive-, anxiety-, and somatic symptom disorders, are the most prevalent mental disorders in later life. Treatment protocols and guidelines largely rely on evidence from RCTs conducted in younger age samples and ignore comorbidity between these disorders. Moreover, studies in geriatric psychiatry are often limited to the “younger old” and rarely include the most frail. Therefore, the effectiveness of treatment in routine clinical care for older patients and impact of ageing characteristics is largely unknown. Objective The primary aim of the Routine Outcome Monitoring for Geriatric Psychiatry & Science (ROM-GPS) – project is to examine the impact of ageing characteristics on the effectiveness of treatment for affective disorders in specialised geriatric mental health care. Methods ROM-GPS is a two-stage, multicentre project. In stage one, all patients aged ≥60 years referred to participating outpatient clinics for specialised geriatric mental health care will be routinely screened with a semi-structured psychiatric interview, the Mini International Neuropsychiatric Interview and self-report symptom severity scales assessing depression, generalized anxiety, hypochondria, and alcohol use. Patients with a unipolar depressive, anxiety or somatic symptom disorder will be asked informed consent to participate in a second (research) stage to be extensively phenotyped at baseline and closely monitored during their first year of treatment with remission at one-year follow-up as the primary outcome parameter. In addition to a large test battery of potential confounders, specific attention is paid to cognitive functioning (including computerized tests with the Cogstate test battery as well as paper and pencil tests) and physical functioning (including multimorbidity, polypharmacy, and different frailty indicators). The study is designed as an ongoing project, enabling minor adaptations once a year (change of instruments). Discussion Although effectiveness studies using observational data can easily be biased, potential selection bias can be quantified and potentially corrected (e.g. by propensity scoring). Knowledge of age-related determinants of treatment effectiveness, may stimulate the development of new interventions. Moreover, studying late-life depressive, anxiety and somatic symptom disorders jointly enables data-driven studies for more optimal classification of these disorders in later life. Trial registration Dutch Trial Register: NL6704 (www.trialregister.nl). Retrospectively registered on 2017-12-05.

Abstract Background At many outpatient departments for psychiatry worldwide, standardized monitoring of the safety of prescribed psychotropic drugs is not routinely performed in daily clinical practice. Therefore it is unclear to which extent the drugs used by psychiatric outpatients are prescribed effectively and safely. These issues warrant structured monitoring of medication use, (pre-existing) co-morbidities, effectiveness and side effects during psychiatric outpatient treatment. Improvement of monitoring practices provides an opportunity to ensure that somatic complications and adverse drug effects are detected and dealt with in a timely manner. Structural support for data collection and follow-up tests seems essential for improvement of monitoring practices in psychiatric outpatients. The implementation of a structured somatic monitoring program as part of routine clinical practice, as we describe in this study protocol, may be a solution. Methods In order to address these issues, we developed the innovative program ‘Monitoring Outcomes of Psychiatric Pharmacotherapy (MOPHAR)’. MOPHAR is an infrastructure for implementation of standardized routine outcome monitoring (ROM; including standardized monitoring of treatment effect), monitoring of adverse psychotropic medication effects in psychiatric outpatients, encompassing both somatic adverse effects (e.g. metabolic disturbances) and subjective adverse effects (e.g. sedation or sexual side effects) and medication reconciliation. Discussion In the MOPHAR monitoring program, a nurse performs general and psychotropic drug-specific somatic screenings and provides the treating mental health care providers with more and better information on somatic monitoring for treatment decisions. Given our experience regarding implementation of the MOPHAR program, we expect that the MOPHAR program is feasible and beneficial for patients in any MHS organisation. This paper describes the objectives, target population, setting and the composition and roles of the treatment team. It also indicates what measurements are performed at which time points during outpatient treatment in the MOPHAR monitoring program, as well as the research aspects of this project. Trial registration MOPHAR research has been prospectively registered with the Netherlands Trial Register on 19th of November 2014. (NL4779).

Abstract Background A subgroup of depressed patients with increased inflammatory activity was shown to be more susceptible to develop Treatment Resistant Depression (TRD). Earlier studies with anti-inflammatory drugs have shown benefits in the treatment of major depressive disorder (MDD), but the effects are expected to be higher in patients with increased inflammatory activity. Supplementation of N-acetylcysteine (NAC) to ongoing antidepressant therapy may positively influence outcome of depression treatment in these patients. Therefore, this study aims to investigate the efficacy of NAC supplementation in patients with insufficient response to standard antidepressant treatment, and to explore potential roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD. Methods/design A double-blind randomized placebo-controlled study comparing NAC versus placebo as add-on medication to antidepressant treatment with 12-week treatment and 8-week follow up in patients with TRD and increased inflammatory activity. Apart from clinical efficacy defined as the change in Hamilton Depression Rating Scale (HAMD)-17 score, secondary outcomes include changes in pathophysiological mechanisms related to depression as well as changes in local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). Importantly, sole patients with CRP levels with values between 0.85 and 10 mg/L will be included. Discussion This is the first clinical trial taking both TRD and increased inflammatory activity as inclusion criteria. This study will provide reliable evidence for the efficacy of NAC in patients with TRD displaying increased inflammatory activity. And this study also will help explore further the roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD. Trial registration The trial protocol has been registered on “ClinicalTrials.gov“with protocol ID “NAC-2015-TJAH” and ClinicalTrials.gov ID “NCT02972398”.

Abstract Background Depression is a leading cause of disability worldwide. To reduce the societal burden and improve quality of life for individual patients, treatments for depression need to be optimized. There is a particular need for person-tailored interventions that reinforce self-management of patients. Systematic self-monitoring and personalized feedback through the Experience Sampling Method (ESM) could provide such a person-tailored, empowering intervention that enhances treatment outcomes. The primary aim of this study is to investigate the efficacy of self-monitoring and personalized feedback as an add-on tool in the treatment of depressive complaints in a natural setting. Methods The ZELF-i study is a pragmatic multi-site randomized controlled trial (RCT). We aim to recruit 150 individuals with depressive symptoms aged between 18 and 65 years, who have an intake for outpatient basic or specialized treatment at a mental health care organization in the North of the Netherlands. After the intake, participants will be randomly allocated to one of three study arms: two experimental groups engaging in 28 days of systematic self-monitoring (5 times per day) and receiving weekly personalized feedback on positive affect and activities (“Do”-module) or on negative affect and thinking patterns (“Think”-module), and a control group receiving no additional intervention. Self-report inventories of depressive symptoms, psychosocial functioning and feelings of empowerment will be administered before and after the intervention period, and at follow-up measurements at 1, 2, 3 and 6 months. The patient-experienced utility of the intervention will be investigated by a combination of quantitative and qualitative research methods. Discussion The present study is the first to examine the effects of add-on self-monitoring and personalized feedback on depressive complaints in clinical practice. It is also the first to evaluate two different ESM modules targeted at both of depression’s core symptoms. Lastly, it is the first study that uses a combination of qualitative and quantitative methods to evaluate the patient-experienced utility of ESM with personalized feedback as an intervention for depression. Results of the present study may improve treatment for depression, if the intervention is found to be effective. Trial registration Dutch Trial Register, NTR5707, registered prospectively 1 February 2016.

Abstract Background Major depressive disorder (MDD) is often handled as an episodic and isolated disorder, resulting in an optimistic view about its prognosis. Herein, we test the idea that the prognosis of MDD changes if we vary the perspective in terms of (1) a longer time frame and (2) a broader diagnostic conceptualisation including dysthymia, (hypo)mania and anxiety disorders as relevant outcomes. Methods Patients with current MDD at baseline (n = 903) and available 2-, 4-, and/or 6-year follow-up assessments were selected from the Netherlands Study of Depression and Anxiety, a psychiatric cohort study. Combining psychiatric DSM-IV-based diagnoses and life-chart data, patient course trajectories were classified as (1) recovered (no diagnoses at 2-year follow-up or thereafter), (2) recurrent without chronic episodes, (3) recurrent with chronic episodes or (4) consistently chronic since baseline. A chronic episode was defined as having a current diagnosis at the follow-up assessment and consistent symptoms over 2 years. Proportions of course trajectories were provided moving from a short, narrow perspective (2-year follow-up, considering only MDD diagnosis) to a long, broad perspective (6-year follow-up, including MDD, dysthymia, (hypo)mania and anxiety diagnoses). Results With the short, narrow perspective, the recovery rate was 58% and 21% had a chronic episode. However, in the long, broad perspective the recovery rate was reduced to 17%, while 55% of the patients experienced chronic episodes. Conclusions Results from a long and rigorous follow-up in a large cohort suggests that most MDD patients have an unfavourable prognosis. Longer follow-up and broader diagnostic conceptualisation show that the majority of patients have a disabling and chronic disorder. Conceptualising and handling MDD as a narrowly defined and episodic disorder may underestimate the prognosis of the majority of depressed patients and, consequently, the type of care that is appropriate.

After publication of our article [1] we were notified that Figure 1 was wrongly presented.