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Background Depression is associated with metabolic alterations including lipid dysregulation, whereby associations may vary across individual symptoms. Evaluating these associations using a network perspective yields a more complete insight than single outcome-single predictor models. Methods We used data from the Netherlands Study of Depression and Anxiety (N = 2498) and leveraged networks capturing associations between 30 depressive symptoms (Inventory of Depressive Symptomatology) and 46 metabolites. Analyses involved 4 steps: creating a network with Mixed Graphical Models; calculating centrality measures; bootstrapping for stability testing; validating central, stable associations by extra covariate-adjustment; and validation using another data wave collected 6 years later. Results The network yielded 28 symptom-metabolite associations. There were 15 highly-central variables (8 symptoms, 7 metabolites), and 3 stable links involving the symptoms Low energy (fatigue), and Hypersomnia. Specifically, fatigue showed consistent associations with higher mean diameter for VLDL particles and lower estimated degree of (fatty acid) unsaturation. These remained present after adjustment for lifestyle and health-related factors and using another data wave. Conclusions The somatic symptoms Fatigue and Hypersomnia and cholesterol and fatty acid measures showed central, stable, and consistent relationships in our network. The present analyses showed how metabolic alterations are more consistently linked to specific symptom profiles.

Abstract Background Patients with schizophrenia experience cognitive impairment, which could be related to neuroinflammation in the hippocampus. The cause for such hippocampal inflammation is still unknown, but it has been suggested that herpes virus infection is involved. This study therefore aimed to determine whether add-on treatment of schizophrenic patients with the anti- viral drug valaciclovir would reduce hippocampal neuroinflammation and consequently improve cognitive symptoms. Methods We performed a double-blind monocenter study in 24 male and female patients with schizophrenia, experiencing active psychotic symptoms. Patients were orally treated with the anti-viral drug valaciclovir for seven consecutive days (8 g/day). Neuroinflammation was measured with Positron Emission Tomography using the translocator protein ligand [11C]-PK11195, pre-treatment and at seven days post-treatment, as were psychotic symptoms and cognition. Results Valaciclovir treatment resulted in reduced TSPO binding (39%) in the hippocampus, as well as in the brainstem, frontal lobe, temporal lobe, parahippocampal gyrus, amygdala, parietal lobe, occipital lobe, insula and cingulate gyri, nucleus accumbens and thalamus (31–40%) when using binding potential (BPND) as an outcome. With total distribution volume (VT) as outcome we found essentially the same results, but associations only approached statistical significance (p = 0.050 for hippocampus). Placebo treatment did not affect neuroinflammation. No effects of valaciclovir on psychotic symptoms or cognitive functioning were found. Conclusion We found a decreased TSPO binding following antiviral treatment, which could suggest a viral underpinning of neuroinflammation in psychotic patients. Whether this reduced neuroinflammation by treatment with valaciclovir has clinical implications and is specific for schizophrenia warrants further research.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression.METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; PCONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Background Previous research has suggested that statistical power is suboptimal in many biomedical disciplines, but it is unclear whether power is better in trials for particular interventions, disorders, or outcome types. We therefore performed a detailed examination of power in trials of psychotherapy, pharmacotherapy, and complementary and alternative medicine (CAM) for mood, anxiety, and psychotic disorders. Methods We extracted data from the Cochrane Database of Systematic Reviews (Mental Health). We focused on continuous efficacy outcomes and estimated power to detect predetermined effect sizes (standardized mean difference [SMD] = 0.20–0.80, primary SMD = 0.40) and meta-analytic effect sizes (ESMA). We performed meta-regression to estimate the influence of including underpowered studies in meta-analyses. Results We included 256 reviews with 10 686 meta-analyses and 47 384 studies. Statistical power for continuous efficacy outcomes was very low across intervention and disorder types (overall median [IQR] power for SMD = 0.40: 0.32 [0.19–0.54]; for ESMA: 0.23 [0.09–0.58]), only reaching conventionally acceptable levels (80%) for SMD = 0.80. Median power to detect the ESMA was higher in treatment-as-usual (TAU)/waitlist-controlled (0.49–0.63) or placebo-controlled (0.12–0.38) trials than in trials comparing active treatments (0.07–0.13). Adequately-powered studies produced smaller effect sizes than underpowered studies (B = −0.06, p ⩽ 0.001). Conclusions Power to detect both predetermined and meta-analytic effect sizes in psychiatric trials was low across all interventions and disorders examined. Consistent with the presence of reporting bias, underpowered studies produced larger effect sizes than adequately-powered studies. These results emphasize the need to increase sample sizes and to reduce reporting bias against studies reporting null results to improve the reliability of the published literature.

Background: Terminally ill patients may experience existential distress, depression, or anxiety, limiting quality of life in the final stage. Existing psychotherapeutic or pharmacological interventions have (time) limited efficacy. Psychedelic treatment may be a safe and effective alternative treatment option. Aim: Systematically review studies on psychedelic treatment with and without psychotherapy for existential distress, depression, and anxiety in terminally ill patients. Methods: Medline, PsycINFO, and Embase were searched for original-data studies on the treatment of depression, anxiety, and existential distress with classical or a-typical psychedelics in patients with a terminal illness, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: A total of 1850 records were screened, and 33 articles were included in this review: 14 studies on classical psychedelics (DPT, LSD, and psilocybin) and 19 studies on atypical psychedelics (MDMA and ketamine). Results of early pre-post studies are promising but have serious methodological flaws. Recent (controlled) trials with LSD, psilocybin, ketamine, and MDMA are of higher methodological quality and indicate positive effects on existential and spiritual well-being, quality of life, acceptance, and reduction of anxiety and depression with few adverse and no serious adverse effects. Conclusions: Both classical and a-typical psychedelics are promising treatment options in patients with terminal illness. To draw final conclusions on effectiveness and safety of psychedelics, we need larger high-quality studies for classical psychedelics and MDMA. Ketamine studies should pay more attention to existential dimensions of well-being and the psychotherapeutic context of the treatment.

Background: Given the strong relationship between depression and anxiety, there is an urge to investigate their shared and specific long-term course determinants. The current study aimed to identify and compare the main determinants of the 9-year trajectories of combined and pure depression and anxiety symptom severity. Methods: Respondents with a 6-month depression and/or anxiety diagnosis (n=1,701) provided baseline data on 152 sociodemographic, clinical and biological variables. Depression and anxiety symptom severity assessed at baseline, 2-, 4-, 6- and 9-year follow-up, were used to identify data-driven course-trajectory subgroups for general psychological distress, pure depression, and pure anxiety severity scores. For each outcome (class-probability), a Superlearner (SL) algorithm identified an optimally weighted (minimum mean squared error) combination of machine-learning prediction algorithms. For each outcome, the top determinants in the SL were identified by determining variable-importance and correlations between each SL-predicted and observed outcome ( ρ p r e d ) were calculated. Results: Low to high prediction correlations ( ρ p r e d : 0.41-0.91, median=0.73) were found. In the SL, important determinants of psychological distress were age, young age of onset, respiratory rate, participation disability, somatic disease, low income, minor depressive disorder and mastery score. For course of pure depression and anxiety symptom severity, similar determinants were found. Specific determinants of pure depression included several types of healthcare-use, and of pure-anxiety course included somatic arousal and psychological distress. Limitations: Limited sample size for machine learning. Conclusions: The determinants of depression- and anxiety-severity course are mostly shared. Domain-specific exceptions are healthcare use for depression and somatic arousal and distress for anxiety-severity course.

Over the past decade, the idiographic approach has received significant attention in clinical psychology, incentivizing the development of novel approaches to estimate statistical models, such as personalized networks. Although the notion of such networks aligns well with the way clinicians think and reason, there are currently several barriers to implementation that limit their clinical utility. To address these issues, we introduce the Prior Elicitation Module for Idiographic System Estimation (PREMISE), a novel approach that formally integrates case formulations with personalized network estimation via prior elicitation and Bayesian inference. PREMISE tackles current implementation barriers of personalized networks; incorporating clinical information into personalized network estimation systematically allows theoretical and data-driven integration, supporting clinician and patient collaboration when building a dynamic understanding of the patient's psychopathology. To illustrate its potential, we estimate clinically informed networks for a patient suffering from obsessive-compulsive disorder. We discuss open challenges in selecting statistical models for PREMISE, as well as specific future directions for clinical implementation. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Item does not contain fulltext 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. 15 p.

Because major depressive disorder (MDD) has a strong negative impact on patients' lives, well–designed treatment programs are needed that address the lasting effects of MDD. Previous work has shown that such programs should not only focus on symptomatic recovery, but also on the subsequent personal recovery process. Currently, few programs with this specific focus exist. Therefore, this study aimed to assess the feasibility of a newly developed blended program to support the personal recovery process of MDD patients: Storytelling and Training to Advance Individual Recovery Skills (STAIRS). STAIRS is a program using peer support and guidance by experts by experience and clinicians, which can be added to regular depression treatment when symptomatic recovery is almost reached. Topics addressed in this program are: (1) effects of depression and treatment; (2) structure; (3) (self) stigma; (4) self-image; (5) meaning of life; (6) connection to others; (7) physical health; (8) relaxation; and (9) preventing relapse. Experiences with the STAIRS program were collected from five participating patients with questionnaires and a focus-group interview, as well as from four trainers using semi-structured interviews. Participants valued the topics addressed in STAIRS, the used working methods, the presence of an expert by experience and the ability to share experiences with peers. The use of an online platform and the involvement of others is seen as potentially supportive but turned out to be more challenging. Perceived effects of STAIRS include positive changes in participants' daily lives and their contacts with others. Overall, the results indicate that when implemented accessibly, STAIRS is a promising and feasible program to foster personal recovery among patients recovering from MDD.

BackgroundThe use of ketamine for depression has increased rapidly in the past decades. Ketamine is often prescribed as an add-on to other drugs used in psychiatric patients, but clear information on drug-drug interactions is lacking. With this review, we aim to provide an overview of the pharmacodynamic interactions between ketamine and mood stabilizers, benzodiazepines, monoamine oxidase-inhibitors, antipsychotics, and psychostimulants.MethodsMEDLINE and Web of Science were searched.ResultsTwenty-four studies were included. For lithium, no significant interactions with ketamine were reported. Two out of 5 studies on lamotrigine indicated that the effects of ketamine were attenuated. Benzodiazepines were repeatedly shown to reduce the duration of ketamine’s antidepressant effect. For the monoamine oxidase-inhibitor tranylcypromine, case reports showed no relevant changes in vital signs during concurrent S-ketamine use. One paper indicated an interaction between ketamine and haloperidol, 2 other studies did not. Four papers investigated risperidone, including 3 neuroimaging studies showing an attenuating effect of risperidone on ketamine-induced brain perfusion changes. Clozapine significantly blunted ketamine-induced positive symptoms in patients with schizophrenia but not in healthy participants. One paper reported no effect of olanzapine on ketamine’s acute psychotomimetic effects.ConclusionCurrent literature shows that benzodiazepines and probably lamotrigine reduce ketamine’s treatment outcome, which should be taken into account when considering ketamine treatment. There is evidence for an interaction between ketamine and clozapine, haloperidol, and risperidone. Due to small sample sizes, different subject groups and various outcome parameters, the evidence is of low quality. More studies are needed to provide insight into pharmacodynamic interactions with ketamine.

Background Apart from cost-effectiveness, considerations like equity and acceptability may affect health-care priority setting. Preferably, priority setting combines evidence evaluation with an appraisal procedure, to elicit and weigh these considerations. Objective To demonstrate a structured approach for eliciting and evaluating a broad range of assessment criteria, including key stakeholders' values, aiming to support decision makers in priority setting. Methods For a set of cost-effective substitute interventions for depression care, the appraisal criteria were adopted from the Australian Assessing Cost-Effectiveness initiative. All substitute interventions were assessed in an appraisal, using focus group discussions and semi-structured interviews conducted among key stakeholders. Results Appraisal of the substitute cost-effective interventions yielded an overview of considerations and an overall recommendation for decision makers. Two out of the thirteen pairs were deemed acceptable and realistic, that is investment in therapist-guided and Internet-based cognitive behavioural therapy instead of cognitive behavioural therapy in mild depression, and investment in combination therapy rather than individual psychotherapy in severe depression. In the remaining substitution pairs, substantive issues affected acceptability. The key issues identified were as follows: workforce capacity, lack of stakeholder support and the need for change in clinicians' attitude. Conclusions Systematic identification of stakeholders' considerations allows decision makers to prioritize among cost-effective policy options. Moreover, this approach entails an explicit and transparent priority-setting procedure and provides insights into the intended and unintended consequences of using a certain health technology. Patient contribution Patients were involved in the conduct of the study for instance, by sharing their values regarding considerations relevant for priority setting.

Background Comorbidity of depressive and anxiety disorders is common and remains incompletely comprehended. This paper summarizes findings from the Netherlands Study of Depression and Anxiety (NESDA) regarding prevalence, temporal sequence, course and longitudinal patterns; sociodemographic, vulnerability and neurobiological indicators; and functional, somatic and mental health indicators of comorbidity. Methods Narrative synthesis of earlier NESDA based papers on comorbidity (n=76). Results Comorbidity was the rule in over three-quarter of subjects with depressive and/or anxiety disorders, most often preceded by an anxiety disorder. Higher severity and chronicity characterized a poorer comorbidity course. Over time, transitions between depressive and anxiety disorders were common. Consistent comorbidity risk indicators in subjects with depressive and anxiety disorders were childhood trauma, neuroticism and early age of onset. Psychological vulnerabilities, such as trait avoidance tendencies, were more pronounced in comorbid than in single disorders. In general, there were few differences in biological markers and neuroimaging findings between persons with comorbid versus single disorders. Most functional, somatic, and other mental health indicators, ranging from disability to cardiovascular and psychiatric multimorbidity, were highest in comorbid disorders. Limitations The observational design of NESDA limits causal inference. Attrition was higher in comorbid relative to single disorders. Conclusions As compared to single disorders, persons with comorbid depressive and anxiety disorders were characterized by more psychosocial risk determinants, more somatic and other psychiatric morbidities, more functional impairments, and poorer outcome. These results justify specific attention for comorbidity of depressive and anxiety disorders, particularly in treatment settings.

Experience sampling studies into daily-life affective reactivity indicate that depressed individuals react more strongly to both positive and negative stimuli than non-depressed individuals, particularly on negative affect (NA). Given the different mean levels of both positive affect (PA) and NA between patients and controls, such findings may be influenced by floor/ceiling effects, leading to violations of the normality and homoscedasticity assumptions underlying the used statistical models. Affect distributions in prior studies suggest that this may have particularly influenced NA-reactivity findings. Here, we investigated the influence of floor/ceiling effects on the observed PA- and NA-reactivity to both positive and negative events. Data came from 346 depressed, non-depressed, and remitted participants from the Netherlands Study of Depression and Anxiety (NESDA). In PA-reactivity analyses, no floor/ceiling effects and assumption violations were observed, and PA-reactivity to positive events, but not negative events, was significantly increased in the depressed and remitted groups versus the non-depressed group. However, NA-scores exhibited a floor effect in the non-depressed group and naively estimated models violated model assumptions. When these violations were accounted for in subsequent analyses, group differences in NA-reactivity that had been present in the naive models were no longer observed. In conclusion, we found increased PA-reactivity to positive events but no evidence of increased NA-reactivity in depressed individuals when accounting for violations of assumptions. The results indicate that affective-reactivity results are very sensitive to modeling choices and that previously observed increased NA-reactivity in depressed individuals may (partially) reflect unaddressed assumption violations resulting from floor effects in NA.

The network approach, in which psychological constructs are modeled in terms of interactions between their constituent factors, have rapidly gained popularity in psychology. Applications of such network approaches to various psychological constructs have recently moved from a descriptive stance, in which the goal is to estimate the network structure, to a more comparative stance, in which the goal is to compare network structures across groups. However, the statistical tools to do so are lacking. In this article, we present the network comparison test (NCT). NCT is a statistical test that compares two network structures on three types of characteristics. Performance of NCT is evaluated by means of a simulation study. Simulated data shows that NCT performs well in various circumstances for all three tests: when the groups are simulated to be similar, the error rate (i.e., NCT indicating that they are different, while the simulated networks are similar) is adequately low, and when the groups are simulated to be different, the ability to detect a difference is sufficiently high when the difference between simulated networks and the sample size are substantial. We illustrate NCT by comparing depression symptom networks of males and females. Possible extensions of NCT are discussed.Network approaches to psychometric constructs, in which constructs are modeled in terms of interactions between their constituent factors, have rapidly gained popularity in psychology. Applications of such network approaches to various psychological constructs have recently moved from a descriptive stance, in which the goal is to estimate the network structure that pertains to a construct, to a more comparative stance, in which the goal is to compare network structures across populations. However, the statistical tools to do so are lacking. In this article, we present the network comparison test (NCT), which uses resampling-based permutation testing to compare network structures from two independent, cross-sectional data sets on invariance of (a) network structure, (b) edge (connection) strength, and (c) global strength. Performance of NCT is evaluated in simulations that show NCT to perform well in various circumstances for all three tests: The Type I error rate is close to the nominal significance level, and power proves sufficiently high if sample size and difference between networks are substantial. We illustrate NCT by comparing depression symptom networks of males and females. Possible extensions of NCT are discussed.

Objective Ketamine has repeatedly shown to have rapid and robust antidepressant effects in patients with treatment resistant depression (TRD). An important question is whether ketamine is as effective and safe as the current gold standard electroconvulsive therapy (ECT). Methods The literature was searched for trials comparing ketamine treatment with ECT for depression in the Pubmed/MEDLINE database and Cochrane Trials Library. Results A total of 137 manuscripts were identified, 6 articles were included in this review. Overall quality of the included studies was diverse with relevant risk of bias for some of the studies. Results suggest that ketamine treatment might give faster but perhaps less durable antidepressant effects. Side effects differed from ECT, in particular less cognitive impairment was apparent in ketamine treatment. Limitations The included studies have limited sample sizes, use different treatment protocols and in most trials, longer term follow up is lacking. Furthermore, allocation bias appears likely in the non-randomized trials. Conclusions Current available literature does not yet provide convincing evidence to consider ketamine as an equally effective treatment alternative to ECT in patients with TRD. There are indications for a more favourable short term cognitive side effect profile after ketamine treatment. Methodologically well-designed studies with larger sample sizes and longer follow up duration are warranted.

Background: Electroconvulsive therapy (ECT) is a potent option for treatment-resistant major depressive disorder (MDD). Cognitive models of depression posit that negative cognitions and underlying all-or-nothing negative schemas contribute to and perpetuate depressed mood. This study investigates whether ECT can modify negative schemas, potentially via memory reactivation, and whether such changes are related to MDD symptom improvement.Method: Seventy-two patients were randomized to either an emotional memory reactivation electroconvulsive therapy (EMR-ECT) or control memory reactivation electroconvulsive therapy (CMR-ECT) intervention prior to ECT-sessions in a randomized controlled trail. Emotional memories associated with patients' depression were reactivated before ECT-sessions. At baseline and after the ECT-course, negative schemas and depression severity were assessed using the Dysfunctional Attitude Scale (DAS) and Hamilton Depression Rating Scale HDRS. Mediation analyses were used to examine whether the effects of ECT on HDRS-scores were mediated by changes in DAS-scores or vice versa.Results: Post-ECT DAS-scores were significantly lower compared to baseline. Post-ECT, the mean HDRS-score of the whole sample (15.10 ± 8.65 [SD]; n = 59) was lower compared to baseline (24.83 ± 5.91 [SD]). Multiple regression analysis showed no significant influence of memory reactivation on schema improvement. Path analysis showed that depression improvement was mediated by improvement of negative cognitive schemas.Conclusion: ECT is associated with improvement of negative schemas, which appears to mediate the improvement of depressive symptoms. An emotional memory intervention aimed to modify negative schemas showed no additional effect.

BACKGROUND: Testosterone has been implicated in suicidality in cross-sectional studies. Stress that coincides with a suicide attempt may alter androgen levels, so prospective studies are needed to exclude reverse causation. We aimed to examine the associations of plasma androgens with concurrent and future suicidality, and if present, whether these associations were mediated by a behavioral trait like reactive aggression.METHODS: Baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulphate with a radioimmunoassay. Suicidality was assessed using the Suicidal Ideation Scale at baseline and after 2-, 4-, 6-, and 9-year follow-up. Men and women were analyzed separately, and potential confounders were considered.RESULTS: Participants (N = 2861; 66.3% women) had a mean age of 42.0 years (range 18-65) and almost half (46.9%) fulfilled criteria for a major depressive or anxiety disorder. At baseline 13.2% of men and 11.2% of women reported current suicidal ideation. In participants who were non-suicidal at baseline, slightly more men than women reported suicidal ideation during follow-up (14.7% vs. 12.5%), whereas the reverse pattern was observed for suicide attempts (3.6% vs. 4.2%). None of the associations between androgens and current and future suicidality were significant.LIMITATIONS: Androgens were determined once, which may have been insufficient to predict suicidality over longer periods.DISCUSSION: The lack of associations between plasma levels of androgens determined by 'gold-standard' laboratory methods with suicidality do not support previous cross-sectional and smaller studies in adult men and women with values within the physiological range.

Background A substantial percentage of depressed patients do not respond satisfactorily to conventional antidepressant treatment. This treatment resistant depression (TRD) may be partly related to inflammatory processes in the central nervous system. Accordingly, peripheral inflammatory markers might serve to predict treatment response with novel but still experimental forms of antidepressant treatment. Methods A literature search on treatment of TRD and inflammatory markers was performed using the PubMed/Medline database on November 8th 2018, and 95 articles were retrieved initially, which were subsequently screened and selected only when the inclusion and exclusion criteria were met. Results Ten studies were recruited. In five studies higher baseline interleukin-6 (IL-6) or C-reactive protein (CRP)/high-sensitivity-CRP (hsCRP) in blood predicted better response to medication with anti-inflammatory characteristics, such as ketamine and infliximab. One study found that higher IL-6 predicted worse response to antidepressant treatment in patients with TRD. No evidence was found for the predictive value of other inflammatory markers (e.g., Tumor Necrosis Factor-α, Interferon-γ). Limitations The number of available studies was limited; included studies showed considerable methodological variation and used different definitions for TRD. Conclusion The inflammatory markers IL-6 and CRP/hsCRP could hold promise as markers for the prediction of treatment response in TRD. Clearly, this field of research is still far from mature but it could pave the way for novel and efficacious treatments for at least the inflammatory type of TRD with more well-designed studies and more convincing results.

Within the field of psychiatry the development of biomarker based assay methods is relatively young. Recent efforts focused on combining several biomarkers within a panel to increase discriminative power. However, most biomarker panels have failed to advance to the stage of clinical application. An important prerequisite is a proper sampling and storage procedure, based on a priori identified stability properties of all biomarker/body fluid combinations present in the panel. Second, is the performance requisites of the assays in use, such as Enzyme-Linked Immunosorbent Assays (ELISA), in order to assure reliable results within and between runs. In this study, we analyzed 24 biomarker assays in 32 biomarker/body fluid combinations. Each biomarker body fluid combination was tested for stability and assay performance. We found hampering stability in almost all cases expect three biomarkers in urine and three in serum. Variability in biomarker stability either indicates decreased biomarker stability or issues in assay performance. This study indicates that basic biomarker/body fluid combination stability provides a good starting point for biomarker panel assay development. However, assay performance plays an important role in the correct interpretation of those results. Along the way of assay development, other quality assurance parameters might be implemented focused on a fit for purpose principle ultimately providing reliable data necessary for diagnostical method implementation.

Terminally ill patients may experience existential distress, depression, or anxiety, limiting quality of life in the final stage. Existing psychotherapeutic or pharmacological interventions have (time) limited efficacy. Psychedelic treatment may be a safe and effective alternative treatment option.Systematically review studies on psychedelic treatment with and without psychotherapy for existential distress, depression, and anxiety in terminally ill patients.Medline, PsycINFO, and Embase were searched for original-data studies on the treatment of depression, anxiety, and existential distress with classical or a-typical psychedelics in patients with a terminal illness, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.A total of 1850 records were screened, and 33 articles were included in this review: 14 studies on classical psychedelics (DPT, LSD, and psilocybin) and 19 studies on atypical psychedelics (MDMA and ketamine). Results of early pre-post studies are promising but have serious methodological flaws. Recent (controlled) trials with LSD, psilocybin, ketamine, and MDMA are of higher methodological quality and indicate positive effects on existential and spiritual well-being, quality of life, acceptance, and reduction of anxiety and depression with few adverse and no serious adverse effects.Both classical and a-typical psychedelics are promising treatment options in patients with terminal illness. To draw final conclusions on effectiveness and safety of psychedelics, we need larger high-quality studies for classical psychedelics and MDMA. Ketamine studies should pay more attention to existential dimensions of well-being and the psychotherapeutic context of the treatment.

BackgroundMost epidemiological studies show a decrease of internalizing disorders at older ages, but it is unclear how the prevalence exactly changes with age, and whether there are different patterns for internalizing symptoms and traits, and for men and women. This study investigates the impact of age and sex on the point prevalence across different mood and anxiety disorders, internalizing symptoms, and neuroticism.MethodsWe used cross-sectional data on 146 315 subjects, aged 18–80 years, from the Lifelines Cohort Study, a Dutch general population sample. Between 2012 and 2016, five current internalizing disorders – major depression, dysthymia, generalized anxiety disorder, social phobia, and panic disorder – were assessed according to DSM-IV criteria. Depressive symptoms, anxiety symptoms, neuroticism, and negative affect (NA) were also measured. Generalized additive models were used to identify nonlinear patterns across age, and to investigate sex differences.ResultsThe point prevalence of internalizing disorders generally increased between the ages of 18 and 30 years, stabilized between 30 and 50, and decreased after age 50. The patterns of internalizing symptoms and traits were different. NA and neuroticism gradually decreased after age 18. Women reported more internalizing disorders than men, but the relative difference remained stable across age (relative risk ~1.7).ConclusionsThe point prevalence of internalizing disorders was typically highest between age 30 and 50, but there were differences between the disorders, which could indicate differences in etiology. The relative gap between the sexes remained similar across age, suggesting that changes in sex hormones around the menopause do not significantly influence women's risk of internalizing disorders.

A recent individual patient data meta-analysis showed that antidepressant medication is slightly more efficacious than cognitive behavioral therapy (CBT) in reducing overall depression severity in patients with a DSM-defined depressive disorder. We used an update of that dataset, based on seventeen randomized clinical trials, to examine the comparative efficacy of antidepressant medication vs. CBT in more detail by focusing on individual depressive symptoms as assessed with the 17-item Hamilton Rating Scale for Depression. Five symptoms (i.e., "depressed mood" , "feelings of guilt" , "suicidal thoughts" , "psychic anxiety" and "general somatic symptoms") showed larger improvements in the medication compared to the CBT condition (effect sizes ranging from .13 to .16), whereas no differences were found for the twelve other symptoms. In addition, network estimation techniques revealed that all effects, except that on "depressed mood" , were direct and could not be explained by any of the other direct or indirect treatment effects. Exploratory analyses showed that information about the symptom-specific efficacy could help in identifying those patients who, based on their pre-treatment symptomatology, are likely to benefit more from antidepressant medication than from CBT (effect size of .30) versus those for whom both treatments are likely to be equally efficacious. Overall, our symptom-oriented approach results in a more thorough evaluation of the efficacy of antidepressant medication over CBT and shows potential in "precision psychiatry" .

BACKGROUND: Neuromodulation is nowadays investigated as a promising method for pain relief. Research indicates that a single 30-minute stimulation with transcranial pulsed electromagnetic fields (tPEMF) can induce analgesic effects. However, it is unknown whether tPEMF can induce analgesia in neuropathic pain patients.OBJECTIVE: To evaluate the effect of tPEMF on spontaneous pain and heat pain in neuropathic pain patients.METHODS: This study had a randomized double-blind crossover design. Twenty neuropathic pain patients received 30-minutes of tPEMF and 30-minutes sham stimulation. Primary outcomes were pain intensity, pain aversion and heat pain. Secondary outcomes included affect, cognition, and motor function, to investigate safety, tolerability and putative working mechanisms of tPEMF. Outcomes were assessed before, during and after stimulation.RESULTS: No differences in analgesic affects between tPEMF and sham stimulation were found for pain intensity, pain aversion or heat pain. No differences between tPEMF and sham stimulation were observed for affect, motor, and cognitive outcomes.CONCLUSION: A single 30-minute tPEMF stimulation did not induce analgesic effects in neuropathic pain patients, compared to sham. Further study is needed to determine whether prolonged stimulation is necessary for analgesic effects.

Research into major depressive disorder (MDD) is complicated by population heterogeneity, which has motivated the search for more homogeneous subtypes through data-driven computational methods to identify patterns in data. In addition, data on biological differences could play an important role in identifying clinically useful subtypes. This systematic review aimed to summarize evidence for biological subtypes of MDD from data-driven studies. We undertook a systematic literature search of PubMed, PsycINFO, and Embase (December 2018). We included studies that identified (1) data-driven subtypes of MDD based on biological variables, or (2) data-driven subtypes based on clinical features (e.g., symptom patterns) and validated these with biological variables post-hoc. Twenty-nine publications including 24 separate analyses in 20 unique samples were identified, including a total of similar to 4000 subjects. Five out of six biochemical studies indicated that there might be depression subtypes with and without disturbed neurotransmitter levels, and one indicated there might be an inflammatory subtype. Seven symptom-based studies identified subtypes, which were mainly determined by severity and by weight gain vs. loss. Two studies compared subtypes based on medication response. These symptom-based subtypes were associated with differences in biomarker profiles and functional connectivity, but results have not sufficiently been replicated. Four out of five neuroimaging studies found evidence for groups with structural and connectivity differences, but results were inconsistent. The single genetic study found a subtype with a distinct pattern of SNPs, but this subtype has not been replicated in an independent test sample. One study combining all aforementioned types of data discovered a subtypes with different levels of functional connectivity, childhood abuse, and treatment response, but the sample size was small. Although the reviewed work provides many leads for future research, the methodological differences across studies and lack of replication preclude definitive conclusions about the existence of clinically useful and generalizable biological subtypes.

Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant\ud depression; disorder severity and unfavorable treatment outcomes are shown to be influenced\ud by an increased genetic burden for major depression (MD). Here, we tested whether ECT assignment\ud and response/nonresponse are associated with an increased genetic burden for major\ud depression (MD) using polygenic risk score (PRS), which summarize the contribution of diseaserelated\ud common risk variants. Fifty-one psychiatric inpatients suffering from a major depressive\ud episode underwent ECT. MD-PRS were calculated for these inpatients and a separate\ud population-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on summary\ud statistics from the Psychiatric Genomics Consortium MDD-working group (Cases:\ud n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease status\ud between ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higher\ud MD-PRS. MD-PRS in population-based depression self-reporters were intermediate between\ud ECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response\ud (50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indicate\ud that ECT cohorts show an increased genetic burden for MD and are consistent with the\ud hypothesis that treatment-resistant MD patients represent a subgroup with an increased genetic\ud risk for MD. Larger samples are needed to better substantiate these findings.

Background: Schizophrenia Spectrum Disorder (SSD) is characterized by its chronic, episodic nature. The clear definition of such episodes is essential for various clinical and research purposes. Most current definitions of episodes in SSD are based on either hospitalizations or on symptom scales. Both have drawbacks; symptom scales are measured infrequently, while hospitalization rates are often affected by policy. This study presents an approach for defining episodes in healthcare data that does not suffer such drawbacks.Methods: Healthcare use of 13,155 SSD patients in the Northern Netherlands with up to 12 years of follow-up was available. Patient-level structural changes in the trend of healthcare use costs were determined using Exponentially Weighted Moving Average (EWMA) control charts. Control charts restart with updated parameters after a detected structural change. Episodes were defined using these structural changes. The resulting episodes were validated by investigating their association with the Global Assessment of Functioning (GAF) scale.Results: The mean number of episodes was 0.61 (sd: 0.60) per patient per year. For the sub-group without hospitalizations this was 0.51 (sd: 0.71). Average episode duration of the sub-group (147 days, sd: 309.4) was similar to that of the full sample (150 days, sd: 305.5). A significant inverse association was identified between GAF scores and the episode-state indicator.Conclusions: The repeated application of EWMA control charts based on healthcare-intensity is a feasible and promising tool for quantifying patient-level healthcare episodes. The validation using GAF scores indicates that our episode indicator is associated with lower levels of global functioning. Results for individuals without hospitalizations indicate that the method is robust with regard to changes in healthcare policy.

BackgroundSleep 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.MethodsWe used AMV (N=17,370) 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.ResultsWe 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-hour [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.ConclusionsWhilst 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.

BACKGROUND Analyzing actigraphy data using standard circadian parametric models and aggregated nonparametric indices may obscure temporal information that may be a hallmark of the circadian impairment in psychiatric disorders. Functional data analysis (FDA) may overcome such limitations by fully exploiting the richness of actigraphy data and revealing important relationships with mental health outcomes. To our knowledge, no studies have extensively used FDA to study the relationship between sociodemographic, health and lifestyle, sampling, and psychiatric clinical characteristics and daily motor activity patterns assessed with actigraphy in a sample of individuals with and without depression/anxiety. OBJECTIVE We aimed to study the association between daily motor activity patterns assessed via actigraphy and (1) sociodemographic, health and lifestyle, and sampling factors, and (2) psychiatric clinical characteristics (ie, presence and severity of depression/anxiety disorders). METHODS We obtained 14-day continuous actigraphy data from 359 participants from the Netherlands Study of Depression and Anxiety with current (n=93), remitted (n=176), or no (n=90) depression/anxiety diagnosis, based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Associations between patterns of daily motor activity, quantified via functional principal component analysis (fPCA), and sociodemographic, health and lifestyle, sampling, and psychiatric clinical characteristics were assessed using generalized estimating equation regressions. For exploratory purposes, function-on-scalar regression (FoSR) was applied to quantify the time-varying association of sociodemographic, health and lifestyle, sampling, and psychiatric clinical characteristics on daily motor activity. RESULTS Four components of daily activity patterns captured 77.4% of the variability in the data: overall daily activity level (fPCA1, 34.3% variability), early versus late morning activity (fPCA2, 16.5% variability), biphasic versus monophasic activity (fPCA3, 14.8% variability), and early versus late biphasic activity (fPCA4, 11.8% variability). A low overall daily activity level was associated with a number of sociodemographic, health and lifestyle, and psychopathology variables: older age (PP=.005), higher BMI (P=.009), greater number of chronic diseases (P=.02), greater number of cigarettes smoked per day (P=.02), current depressive and/or anxiety disorders (P=.05), and greater severity of depressive symptoms (PP=.02) and summer (reference: winter; P=.03). Earlier morning activity was associated with older age (P=.02), having a partner (P=.009), work/school days (PP=.02 and PP=.005). Biphasic activity was associated with work/school days (PPP=.005), work/school days (PPP=.005, respectively). In FoSR analyses, age, work/school days, and season were the main determinants having a time-varying association with daily motor activity (all P CONCLUSIONS Features of daily motor activity extracted with fPCA reflect commonly studied factors such as the intensity of daily activity and preference for morningness/eveningness. The presence and severity of depression/anxiety disorders were found to be associated mainly with a lower overall activity pattern but not with the time of the activity. Age, work/school days, and season were the variables most strongly associated with patterns and time of activity, and thus future epidemiological studies on motor activity in depression/anxiety should take these variables into account.

BackgroundAlthough symptomatic remission is considered the optimal outcome in depression, this is not always achieved. Furthermore, symptom indicators do not fully capture patients’ and clinicians’ perspectives on remission. Broader indicators of (partial) remission from depression should be considered.AimsTo investigate relevant outcomes of depression treatment in specialist care from patients’ and clinicians’ perspectives and to investigate whether these perspectives differ from each other.MethodThree focus groups with 11 patients with depression and seven semi-structured interviews with clinicians were conducted exploring their perspectives on remission. All interviews were audio-recorded and transcribed verbatim. We analysed the transcripts thematically using the phenomenologist approach.ResultsIndependently, both patients and clinicians perceived the following outcomes relevant: restoring social functioning and interpersonal relations, regaining quality of life and achieving personal goals. All clinicians emphasised symptom reduction and satisfaction with treatment as relevant outcomes, whereas the former was not an obvious theme in patients. Unlike clinicians, patients made a clear distinction between treatment outcomes in first versus recurrent/chronic depression.ConclusionsClassically defined study outcomes based on symptom resolution only partly reflect issues considered important by patients and clinicians in specialist depression treatment. Incorporating patients’ and clinicians’ perspectives in the development of measurable end-points makes them more suitable for use in trials and subsequent translation to clinical practice. Furthermore, evaluating patients’ perspectives on treatment outcomes helps in the development of tailored interventions according to patients’ needs.

Importance: Although electroconvulsive therapy (ECT) is often effective, approximately half of patients with depression undergoing ECT do not benefit sufficiently, and relapse rates are high. ECT sessions have been shown to weaken reactivated memories. The effect of emotional memory retrieval on cognitive schemas remains unknown. Objective: To assess whether emotional memory retrieval just before patients receive ECT sessions weakens underlying cognitive schemas, improves ECT effectiveness, increases ECT response, and reduces relapse rates. Design, Setting, and Participants: In this multicenter randomized clinical trial conducted from 2014 to 2018 in the departments of psychiatry in 3 hospitals in the Netherlands, 72 participants were randomized 1:1 to 2 parallel groups to receive either emotional memory reactivation (EMR-ECT) or control memory reactivation (CMR-ECT) interventions before ECT sessions. The Hamilton Depression Rating Scale (HDRS [total score range: 0-52, with 0-7 indicating no depression and ≥24 indicating severe depression]) was used to measure symptoms of depression during and after ECT, with a 6-month follow-up period. Participants were between ages 18 and 70 years with a primary diagnosis of unipolar major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) and in whom ECT was indicated. Data analysis was performed from July to November 2019. Interventions: EMR-ECT or CMR-ECT interventions prior to ECT sessions. Main Outcomes and Measures: Depression scores and relapse rates within 6 months were assessed with the HDRS and analyzed using logistic and linear multiple regression analyses. Results: A total of 66 patients (mean [SD] age, 49.3 [12.3] years; 39 [59.1%] women) were randomized to the EMR-ECT group (n = 32) or the CMR-ECT group (n = 34). Regardless of the memory intervention, 42.4% (28 of 66) of patients responded (≥50% decrease of symptom severity on the HDRS). Of patients who responded, 39.3% (11 of 28) relapsed within 6 months. Remission rates (CMR-ECT group, 29.4% [10 of 34] vs EMR-ECT group, 25.0% [8 of 32]; P = .58), mean (SD) HDRS scores after the ECT course (CMR-ECT group, 14.6 [8.6] vs EMR-ECT group, 14.9 [8.8]; P = .88), total mean (SD) number of required ECT sessions for response (CMR-ECT group, 14.9 [7.9] vs EMR-ECT group, 15.6 [7.3]; P = .39), and relapse rates (CMR-ECT group, 46.7% [7 of 15] vs EMR-ECT group, 30.8% [4 of 13]; P = .33) were not significantly altered by the intervention. Conclusions and Relevance: Study findings suggest that the EMR-ECT intervention just before patient receipt of ECT for depression did not improve effectiveness, increase speed of response, or reduce relapse rates after the ECT course compared with patients receiving CMR-ECT. Trial Registration: Trialregister.nl Identifier: NL4289.

Objective Clinical characteristics appear limited in their ability to predict course of anxiety disorders, therefore we explored the predictive value of biological parameters on course of anxiety disorders. Methods 907 persons with an anxiety (panic, social phobia, generalised anxiety) disorder with a baseline and two-year follow-up measure were selected from the Netherlands Study of Depression and Anxiety (NESDA). Previously, three course trajectories were distinguished which vary in terms of symptom severity and chronicity. Baseline clinical parameters like anxiety severity, anxiety duration, and disability were limited in their ability to predict the two-year course. This study explored whether metabolic syndrome, hypothalamic-pituitary-adrenal-axis functioning, inflammation markers, and neuroplasticity were indicators of two-year course and whether these parameters improved the model containing the most predictive clinical parameters only. Results Baseline diastolic blood pressure of persons with chronic moderate symptoms was significantly higher than of persons with non-chronic mild symptoms (odds ratio [OR] = 1.18, 95% confidence interval [CI95%] 1.01 to 1.38). Baseline high-density lipid cholesterol of persons with severe chronic symptoms was significantly lower than of persons with non-chronic mild symptoms (OR = 0.77, CI95% 0.62 to 0.96). The predictive ability of both parameters was however low with concordance statistics of 0.55 and 0.57 respectively. Addition of biological parameters did not improve the predictive ability of the model containing the clinical parameters. Conclusions In addition to clinical characteristics, biological parameters did not improve the predictive ability of the model for course trajectory of anxiety disorders. Prediction of course trajectory in anxiety disorders remains difficult and warrants further research.

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.

Background: Attention Deficit Hyperactivity Disorder (ADHD) is highly prevalent in patients with a substance use disorder (SUD). Because of possible problems with validity, diagnostic assessment of ADHD is usually postponed until after a period of abstinence, which may jeopardize adequate and timely treatment. The aim of this study is to investigate how a diagnostic assessment of ADHD in patients who are actively using substances compares to the results of a second assessment after a period of full or partial abstinence.Methods: Prospective test-retest study in a SUD treatment center among 127 treatment seeking adult SUD patients with a comorbid diagnosis of adult ADHD. Conners' Adult ADHD Diagnostic Interview for DSM-IV was administered at intake and after four SUD treatment sessions.Results: The mean time interval between intake and retest assessment was 78 days (SD = 32; range 31-248). At the second ADHD assessment, substance use had decreased to about 50% of baseline consumption. Of the 127 patients with an initial diagnosis of ADHD, 121 patients (95.3%) still fulfilled DSM-IV adult ADHD criteria at re diagnosis. Subtyping of ADHD was less stable (Cohen's Kappa = 0.53). Agreement on the number of childhood and adult ADHD symptoms between both assessments was good (intraclass correlation coefficient of 0.69 and 0.65, respectively). Sensitivity analyses in subgroups of patients who were fully abstinent during the second assessment yielded very similar results.Conclusions: These findings strongly suggest that a pragmatic approach, in which patients are evaluated for ADHD even when they are not (yet) abstinent, is feasible and justifiable.

BACKGROUND Smartphones have become ubiquitous in China, offering a promising way to deliver mental health interventions; however, little is known about the current use and characteristics of smartphone apps for mental health. OBJECTIVE The purpose of this study was to gain insight into mobile mental health apps available in China as of December 2018. METHODS A systematic search was conducted to identify and evaluate the most downloaded apps from iOS and Android platforms. Apps were categorized according to their main purpose and downloaded to evaluate their content. Each app’s affiliation, cost, target users, information security, and evidence-based nature were evaluated. RESULTS Of the 172 unique apps that were identified, there were 37 apps (21.5%) for psychological counseling, 50 apps (29.1%) for assessment, 12 apps (7.0%) to relieve stress, 24 apps (14.0%) for psychoeducation, and 49 (28.4%) multipurpose apps (ie, a combination of counseling and assessment). Most apps were developed for adults in the general population (166/172, 96.5%), rather than for psychiatric patients. App-based counseling was mostly provided by psychologists, and of the assessed apps, only 40% (70/172) used evidence-based scales to assess mental health problems such as anxiety or depressed mood. Guided meditation was used as the main technique in stress-relieving apps. CONCLUSIONS Many apps contained useful and evidence-based elements, such as good quality information, validated measurements, and useful meditation methods; however, for mobile apps to contribute significantly to mental health care in China, considerable challenges remain, including the need for more patient-focused apps that can actually take on the role of a health care provider. In addition, efficacy studies are needed.

Highlights • Connectivity analyses complemented with a metric exploring switching in brain activity. • Lower insula-salience connectivity predicts insufficient antidepressant response. • This same insula region is activated less when switching from task to a rest. • This could be a potential biomarkers for predicting future antidepressant response., Insufficient response to treatment is the main cause of prolonged suffering from major depressive disorder (MDD). Early identification of insufficient response could result in faster and more targeted treatment strategies to reduce suffering. We therefore explored whether baseline alterations within and between resting state functional connectivity networks could serve as markers of insufficient response to antidepressant treatment in two years of follow-up. We selected MDD patients (N = 17) from the NEtherlands Study of Depression and Anxiety (NESDA), who received ≥ two antidepressants, indicative for insufficient response, during the two year follow-up, a group of MDD patients who received only one antidepressant (N = 32) and a healthy control group (N = 19) matched on clinical characteristics and demographics. An independent component analysis (ICA) of baseline resting-state scans was conducted after which functional connectivity within the components was compared between groups. We observed lower connectivity of the right insula within the salience network in the group with ≥ two antidepressants compared to the group with one antidepressant. No difference in connectivity was found between the patient groups and healthy control group. Given the suggested role of the right insula in switching between task-positive mode (activation during attention-demanding tasks) and task-negative mode (activation during the absence of any task), we explored whether right insula activation differed during switching between these two modes. We observed that in the ≥2 antidepressant group, the right insula was less active compared to the group with one antidepressant, when switching from task-positive to task-negative mode than the other way around. These findings imply that lower right insula connectivity within the salience network may serve as an indicator for prospective insufficient response to antidepressants. This result, supplemented by the diminished insula activation when switching between task and rest related networks, could indicate an underlying mechanism that, if not sufficiently targeted by current antidepressants, could lead to insufficient response. When replicated, these findings may contribute to the identification of biomarkers for early detection of insufficient response.

The current chapter discusses different aspects of treatment resistance in mental disorders. We will first describe the prevalence and disease burden of mental disorders, then we will have a closer look at treatment outcomes in psychiatry, and next we will focus on treatment resistance, its impact and strategies for improvement. It will become clear that, despite the rapidly increasing knowledge base for psychiatric treatments, there are still many unknowns and points for improvement. The aim of this chapter is to introduce the major elements of this discussion needed to appreciate the more specific aspects that will be treated in the subsequent chapters that focus on specific disorders.

Lower physical activity and sleep problems are linked to depressive and anxiety disorders and can be assessed objectively with wrist-worn actigraphy devices that measure gross motor activity. Standard methods to model 24-h actigraphy are often based on summary measures such as activity counts per day or parametric functional curves (e.g., cosinor functions), losing important information that may be a hallmark of the circadian impairment in psychiatric disorders. Functional Principal Component Analysis (fPCA), a powerful data-driven technique, may better describe daily activity patterns and provide a greater insight into the relationship with depression and anxiety. We assessed patterns of daily activity extracted with fPCA and will evaluate how they are associated with DSM-IV depression and anxiety disorders. Two-week actigraphy data of 367 participants with current (n=94), remitted (n=176) or no (n=90) depression and/or anxiety were obtained from the Netherlands Study of Depression and Anxiety. Daily minute-to-minute activity data were represented with a set of nine Fourier-based functions and summarized with a smaller set of functional principal components with the R package fda. Preliminary analyses resulted in four functional principal components explaining 77.4% of variability (Fig. 1): 1) fPCA1 represented high (+) versus dampened and shifted delayed (-) activity; 2) fPCA2 described morning (+) versus evening (-) activity; 3) fPCA3 showed biphasic (+) versus monophasic (-) activity; 4) fPCA4 represented biphasic morning (+) versus biphasic evening (-) activity. First analyses on the association of the extracted features with depression and anxiety using GEE analysis seem to indicate that current depression and anxiety are significantly associated with lower fPCA1 (?= -0.298, standard error (se) = 0.042, p = 0.006) but not with the other components. Further analyses will be conducted to evaluate if specific depression and anxiety characteristics (e.g. age of onset, duration, comorbidity) are associated with the components.

OBJECTIVE: While the new DSM-5 anxious distress specifier is of great clinical importance, no evidence exists for its longitudinal predictive validity for clinical outcomes in patients with major depressive disorder (MDD). We examined the longitudinal validity of this specifier and validated it against DSM-IV-based comorbid anxiety disorder diagnoses. METHODS: Data are from 1,080 patients with current MDD at baseline (September 2004 to February 2007), of which 911 participated in the 2-year follow-up (September 2006 to April 2009). Patients are from the Netherlands Study of Depression and Anxiety, which is an ongoing longitudinal cohort study, and were sampled from the community, primary care, and outpatient specialized care settings. The specifier was constructed in the existing sample by 5 matching self-report items. Predictive outcomes were 2-year chronicity, time to remission of MDD, and functional disability. Discriminant performance and convergent validity of the specifier were also assessed. RESULTS: The specifier was present in 54.2% of the sample. The specifier significantly outperformed anxiety disorders in predicting chronicity (OR = 1.96, P < .001, vs OR = 1.11, P = .49), time to remission of MDD (HR = 0.75, P = .002, vs HR = 0.94, P = .55), and functional disability (B = 10.03, P < .001, vs B = 2.53, P = .07). The specifier significantly discriminated in clinical characteristics, had convergent validity for anxiety characteristics, and poorly overlapped with DSM-IV-based anxiety disorder diagnoses (Cohen κ = .09). CONCLUSIONS: The short anxious distress specifier outperforms DSM-IV-based anxiety disorder diagnoses as a longitudinal predictor for clinical outcomes in patients with MDD.

Rationale Major depressive disorder (MDD) has been associated with disturbances in social functioning and in the brain serotonin system. Reduced levels of serotonin may negatively influence social functioning, for example by impairing the recognition of facial emotion expressions. Objectives The present study investigated the effect of acute tryptophan depletion (ATD), which reduces brain serotonin, on a related component of social functioning, empathic accuracy (EA), and oxytocin levels. Methods Individuals with (FH+) and without (FH−) a family history of MDD participated in a randomized, double-blind, crossover study. On two separate test days, participants ingested tryptophan-deficient and nutritionally balanced amino acid mixtures. Six hours later, they performed an EA task, which involved watching videos of people recounting autobiographical emotional events. While watching, participants continuously rated how these people felt during the recounting. Mood state was repeatedly assessed using the Positive Affect and Negative Affect Schedule and a series of visual analogue scales. Blood samples obtained at baseline and 5 h after mixture ingestion were assessed for tryptophan and oxytocin levels. Results ATD decreased circulating levels of tryptophan and oxytocin. Nevertheless, there were no significant effects of ATD on EA or mood in either FH group. Conclusions While previous studies have shown that acute reductions in brain serotonin alter the recognition of facial emotion expressions in never-depressed individuals, the present study suggests that empathic abilities may remain unaffected. Electronic supplementary material The online version of this article (doi:10.1007/s00213-015-4093-9) contains supplementary material, which is available to authorized users.

Background: Stability of diagnosis was listed as an important predictive validator for maintaining separate diagnostic classifications in DSM-5. The aim of this study is to examine the longitudinal stability of anxiety disorder diagnoses, and the difference in stability between subjects with a chronic versus a nonchronic course.Methods: Longitudinal data of 447 subjects with a current pure anxiety disorder diagnosis at baseline from the Netherlands Study of Depression and Anxiety were used. At baseline, 2-, 4-, and 6-year followup mental disorders were assessed and numbers (and percentages) of transitions from one anxiety disorder diagnosis to another were determined for each anxiety disorder diagnosis separately and for subjects with a chronic (i.e. one or more anxiety disorder at every follow-up assessment) and a nonchronic course.Results: Transition percentages were high in all anxiety disorder diagnoses, ranging from 21.1% for social anxiety disorder to 46.3% for panic disorder with agoraphobia at six years of follow-up. Transition numbers were higher in the chronic than in the non-chronic course group (p=0.01).Limitations: Due to the 2 year sample frequency, the number of subjects with a chronic course may have been overestimated as intermittent recovery periods may have been missed.Conclusions: These data indicate that anxiety disorder diagnoses are not stable over time. The validity of the different anxiety disorder categories is not supported by these longitudinal patterns, which may be interpreted as support for a more pronounced dimensional approach to the classification of anxiety disorders. (C) 2015 Elsevier B.V. All rights reserved.

Background: To review how daily symptom ratings have been used in research into premenstrual dysphoric disorder (PMDD), and to discuss opportunities for the future. Methods: PsycINFO and Medline were systematically searched, resulting in the inclusion of 75 studies in which (1) participants met the diagnostic criteria for late luteal phase dysphoric disorder (LLPDD) or PMDD and (2) diaries were used to study LLPDD/PMDD. Results: To date, diaries have been used to gain insight into the aetiology and phenomenology of PMDD, to examine associated biological factors, and to assess treatment efficacy. We found low consistency among the diaries used, and often only part of the menstrual cycle was analysed instead of the whole menstrual cycle. We also observed that there was substantial variability in diagnostic procedures and criteria. Limitations: This review excluded diary studies conducted in women with premenstrual syndrome, women seeking help for premenstrual complaints without a clear diagnosis, and women without premenstrual complaints. Conclusions: Prospective daily ratings of symptoms and related variables provide a valuable and important tool in the study of PMDD. This paper addresses some options for improving the use of diaries and proposes the use of experience sampling and ecological momentary assessment to investigate within-person variability in symptoms in more detail. (C) 2015 Elsevier B.V. All rights reserved.

BACKGROUND: High rates of psychiatric comorbidity are subject of debate: To what extent do they depend on classification choices such as diagnostic thresholds? This paper investigates the influence of different thresholds on rates of comorbidity between major depressive disorder (MDD) and generalized anxiety disorder (GAD). METHODS: Point prevalence of comorbidity between MDD and GAD was measured in 74,092 subjects from the general population (LifeLines) according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria. Comorbidity rates were compared for different thresholds by varying the number of necessary criteria from ≥1 to all nine symptoms for MDD, and from ≥1 to all seven symptoms for GAD. RESULTS: According to DSM thresholds, 0.86% had MDD only, 2.96% GAD only, and 1.14% both MDD and GAD (odds ratio (OR) 42.6). Lower thresholds for MDD led to higher rates of comorbidity (1.44% for ≥4 of nine MDD symptoms, OR 34.4), whereas lower thresholds for GAD hardly influenced comorbidity (1.16% for ≥3 of seven GAD symptoms, OR 38.8). Specific patterns in the distribution of symptoms within the population explained this finding: 37.3% of subjects with core criteria of MDD and GAD reported subthreshold MDD symptoms, whereas only 7.6% reported subthreshold GAD symptoms. CONCLUSIONS: Lower thresholds for MDD increased comorbidity with GAD, but not vice versa, owing to specific symptom patterns in the population. Generally, comorbidity rates result from both empirical symptom distributions and classification choices and cannot be reduced to either of these exclusively. This insight invites further research into the formation of disease concepts that allow for reliable predictions and targeted therapeutic interventions. Language: en

Following publication of this article, the authors noticed an error in Supplementary Table 1. In the original Supplementary Table 1, one of the criteria for control participants was incorrectly given as ‘Report extensive recent symptoms of depression: less than 14 on summed response (where “not at all” = 1 and “nearly every day” = 4) to recent’. This has now been corrected to: ‘Report extensive recent symptoms of depression: less than 5 on summed response (where “not at all” = 1 and “nearly every day” = 4) to recent’.

Functional Somatic Symptoms (FSS) are somatic symptoms for which no somatic cause can be identified despite adequate diagnostic testing. FSS are common, costly, and disabling, and treatment options are limited. Psychotherapy is one of few evidence-based treatments for FSS. Yet, this form of therapy is not widely used, since it is usually reserved for severe symptoms, requires a highly trained therapist, and is not well accepted by patients. The current paper describes the development of the online intervention ‘Grip self-help’ and provides a description of the intervention itself. Grip self-help is an early intervention for mild to moderate FSS in primary care, which aims to reduce somatic symptoms and improve quality of life. In the Grip self-help intervention, patients fill out a set of online questionnaires exploring unhelpful cognitions, emotions, behaviors, and social factors associated with the symptoms. Using this information, a personal profile is generated, identifying factors that might maintain FSS in that individual. As a next step, patients are offered online self-help exercises that are tailored to these factors. Guidance is offered by a primary care professional. The intervention will ultimately result in a personalized self-help guide, composed of texts that are extracted from the exercises patients found useful during the intervention. Grip self-help is the first intervention for FSS combining the concepts of e-health, self-help, and personalized medicine. Guided by a primary care professional, patients are offered an easily accessible, yet highly personalized treatment. Grip self-help thus has the potential to meet the needs of the large group of patients with mild to moderate FSS., Highlights • FSS are somatic symptoms for which no somatic cause can be identified despite adequate diagnostic investigations. • Psychotherapy is an evidence-based treatment for FSS, but is not available, effective or acceptable to all patients. • We describe the development of the person-tailored online intervention ‘Grip self-help’. • Grip self-help uses automated personal profiling to select person-tailored self-help exercises. • The underlying personalization algorithms are constructed based on the input of clinicians experienced in FSS treatments. • Grip self-help has the potential to improve early intervention for mild to moderate FSS in primary care.