Identification of latent classes in mood and anxiety disorders and their transitions over time: a follow-up study in the adult general population.

BACKGROUND: Mood and anxiety disorders are heterogeneous conditions with variable course. Knowledge on latent classes and transitions between these classes over time based on longitudinal disorder status information provides insight into clustering of meaningful groups with different disease prognosis. METHODS: Data of all four waves of the Netherlands Mental Health Survey and Incidence Study-2 were used, a representative population-based study of adults (mean duration between two successive waves = 3 years; N at T0 = 6646; T1 = 5303; T2 = 4618; T3 = 4007; this results in a total number of data points: 20 574). Presence of eight mood and anxiety DSM-IV disorders was assessed with the Composite International Diagnostic Interview. Latent class analysis and latent Markov modelling were used. RESULTS: The best fitting model identified four classes: a healthy class (prevalence: 94.1%), depressed-worried class (3.6%; moderate-to-high proportions of mood disorders and generalized anxiety disorder (GAD)), fear class (1.8%; moderate-to-high proportions of panic and phobia disorders) and high comorbidity class (0.6%). In longitudinal analyses over a three-year period, the minority of those in the depressed-worried and high comorbidity class persisted in their class over time (36.5% and 38.4%, respectively), whereas the majority in the fear class did (67.3%). Suggestive of recovery is switching to the healthy class, this was 39.7% in the depressed-worried class, 12.5% in the fear class and 7.0% in the high comorbidity class. CONCLUSIONS: People with panic or phobia disorders have a considerably more persistent and chronic disease course than those with depressive disorders including GAD. Consequently, they could especially benefit from longer-term monitoring and disease management.

The Effects of Patient Preference on Clinical Outcome, Satisfaction and Adherence Within the Treatment of Anxiety and Depression: A Meta-Analysis.

BACKGROUND: Taking patient preference into consideration has received increased attention in the last decades. We conducted a meta-analysis to estimate the effects of patient preference on clinical outcome, satisfaction and adherence regarding treatment of depression and anxiety. METHODS: Pubmed, Embase, PsycINFO and Scopus were searched for (cluster) randomized controlled trials. Twenty-six randomized controlled clinical trials were included, comprising 3670 participants, examining the effect of patient preference regarding treatment of anxiety and depression on clinical outcome, satisfaction and/or adherence. RESULTS: No effect of patient preference was found on clinical outcome [d = 0.06, 95% CI = (-0.03, 0.15), p = 0.16, n = 23 studies]. A small effect of patient preference was found on treatment satisfaction [d = 0.33, 95% CI = (0.08, 0.59), p = 0.01, n = 6 studies] and on treatment adherence [OR = 1.55, 95% CI = (1.28, 1.87), p < 0.001, n = 22 studies]. LIMITATIONS: Patient preference is a heterogeneous concept, future studies should strive to equalize operationalization of preference. Subgroup analyses within this study should be interpreted with caution because the amount of studies per analysed subgroup was generally low. Most studies included in this meta-analysis focused on patients with depression. The small number of studies (n = 6) on satisfaction, prevents us from drawing firm conclusions. CONCLUSIONS: While this meta-analysis did not find a positive effect of considering patient preference on clinical outcome, it was associated with slightly better treatment satisfaction and adherence. Accommodating preference of patients with anxiety and depression can improve treatment. TRIAL REGISTRATION: PROSPERO: CRD42020172556.

Risk factors of chronic course of anxiety and depressive disorders: a 3-year longitudinal study in the general population.

BACKGROUND: Risk factors of a chronic course of anxiety and depressive disorders were previously studied using a limited definition of recovery, i.e. remission of the index disorder. However, frequently, other mental disorders are present at follow-up. Thus, the course of anxiety and depressive disorders was represented too rosy and the identified determinants may not apply when using a broader, more realistic definition. Additionally, physical health risk factors have often been ignored. METHODS: Data were used from two waves of the Netherlands Mental Health Survey and Incidence Study-2 including 509 respondents with 12-month anxiety disorder (panic disorder, social phobia, agoraphobia or generalized anxiety disorder) or/and major depressive disorder at baseline. Chronic course was defined as (1) presence of index disorder; and (2) presence of any anxiety, mood or substance use disorder (overall course) during the subsequent three years. Regression models were built with sociodemographic, clinical, and lifestyle/physical health indicators. Predictive accuracy was evaluated with area under the curve (AUC). RESULTS: Chronic course of the index disorder was present among 24.8% of cases, whereas 38.7% had a chronic overall course. The accuracy of prediction of chronic course of the index disorder was suboptimal (AUC = 0.68) compared to prediction of overall course (AUC = 0.75). The main risk factors were baseline number of mental disorders, neuroticism, childhood abuse, parental psychopathology and alcohol use. Lifestyle and physical health indicators were marginally relevant. CONCLUSION: Transdiagnostic risk factors are important in predicting overall course of anxiety and depressive disorders but cannot accurately predict chronic course of the index disorder.

Schema therapy with cognitive behaviour day-treatment in patients with treatment-resistant anxiety disorders and obsessive-compulsive disorder: an uncontrolled pilot study.

BACKGROUND: Treatment resistance in patients with anxiety disorders and obsessive-compulsive disorder (OCD) might be caused by dysfunctional personality traits or, more specifically, early maladaptive schemas (EMSs) and schema modes, that can be treated with schema therapy (ST). AIM: To explore possible effectiveness of ST-CBT day-treatment in patients with treatment-resistant anxiety disorders and OCD in an uncontrolled pilot study. METHOD: Treatment-resistant patients with anxiety disorders or OCD (n = 27) were treated with ST-CBT day-treatment for 37 weeks on average including 11.5 therapy hours per week. The Symptom Questionnaire-48, Young Schema Questionnaire-2 and Schema Mode Inventory were completed before and after treatment. RESULTS: General psychopathology, EMSs and schema modes significantly improved after treatment. Spearman's correlations between pre- to post-treatment difference scores of general psychopathology, EMSs and schema modes were significant and high. The level of pre-treatment EMSs and schema modes did not predict post-treatment general psychopathology. CONCLUSIONS: Symptom reduction was strongly correlated with improvement of EMSs and schema modes. Stronger pre-treatment EMSs and schema modes did not hinder improvement of symptoms. ST-CBT day-treatment is promising for patients with treatment-resistant anxiety disorders and OCD. Further controlled research is needed to substantiate evidence for schema therapy in patients with treatment-resistant anxiety disorders and OCD.

Predicting the naturalistic course in anxiety disorders using clinical and biological markers: a machine learning approach.

BACKGROUND: Disease trajectories of patients with anxiety disorders are highly diverse and approximately 60% remain chronically ill. The ability to predict disease course in individual patients would enable personalized management of these patients. This study aimed to predict recovery from anxiety disorders within 2 years applying a machine learning approach. METHODS: In total, 887 patients with anxiety disorders (panic disorder, generalized anxiety disorder, agoraphobia, or social phobia) were selected from a naturalistic cohort study. A wide array of baseline predictors (N = 569) from five domains (clinical, psychological, sociodemographic, biological, lifestyle) were used to predict recovery from anxiety disorders and recovery from all common mental disorders (CMDs: anxiety disorders, major depressive disorder, dysthymia, or alcohol dependency) at 2-year follow-up using random forest classifiers (RFCs). RESULTS: At follow-up, 484 patients (54.6%) had recovered from anxiety disorders. RFCs achieved a cross-validated area-under-the-receiving-operator-characteristic-curve (AUC) of 0.67 when using the combination of all predictor domains (sensitivity: 62.0%, specificity 62.8%) for predicting recovery from anxiety disorders. Classification of recovery from CMDs yielded an AUC of 0.70 (sensitivity: 64.6%, specificity: 62.3%) when using all domains. In both cases, the clinical domain alone provided comparable performances. Feature analysis showed that prediction of recovery from anxiety disorders was primarily driven by anxiety features, whereas recovery from CMDs was primarily driven by depression features. CONCLUSIONS: The current study showed moderate performance in predicting recovery from anxiety disorders over a 2-year follow-up for individual patients and indicates that anxiety features are most indicative for anxiety improvement and depression features for improvement in general.

Barriers and facilitators for treatment-seeking in adults with a depressive or anxiety disorder in a Western-European health care setting: a qualitative study.

BACKGROUND: Previous research on barriers and facilitators regarding treatment-seeking of adults with depressive and anxiety disorders has been primarily conducted in the Anglosphere. This study aims to gain insight into treatment-seeking behaviour of adults with depressive and anxiety disorders in a European healthcare system. METHODS: In-depth semi-structured interviews were conducted with 24 participants, aged ≥18 years and diagnosed with an anxiety disorder and/or depressive disorder according to DSM-IV. Participants were purposively sampled from an outpatient department for mental health care in the Netherlands. The seven steps of framework analysis were used to identify relevant themes emerging from the interviews. RESULTS: Data analysis suggested an interplay between individual aspects, personal social system, healthcare system and sociocultural context influences. Amongst the most relevant themes were mental health illiteracy, stigma, a negative attitude toward professional help, the influence of significant others and general practitioner, and waiting time. Financial barriers were not of relevance. CONCLUSIONS: Even in a country with a well-developed mental health care system and in absence of financial barriers, there are many barriers to treatment-seeking in adult patients with depressive and anxiety disorders. National campaigns to increase awareness and decrease stigma in the general population, and to empower the social environment might reduce the treatment gap.

Duration of anxiety disorder and its associated risk indicators: Results of a longitudinal study of the general population.

BACKGROUND: Data on episode duration of anxiety disorders are required for informing patients and for disease management, but such data from population studies are lacking. METHODS: Three-year longitudinal data were used from the Netherlands Mental Health Survey and Incidence Study-2, a psychiatric epidemiological cohort study among the general adult population (N = 6646). Respondents with a new (first or recurrent) anxiety disorder were selected (n = 158). DSM-IV diagnoses were assessed with the Composite International Diagnostic Interview; the Life Chart Interview assessed episode duration and recovery rates. RESULTS: Among those with anxiety disorder, median episode duration was 7.5 months and mean duration was 15.2 months. 38.8% had not recovered at 12 months and 30.1% not at 36 months. Longer duration was associated with older age, not having a paid job, higher neuroticism, more physical disorders, and worse physical functioning. CONCLUSIONS: Also, in the general population, anxiety disorder has a rather chronic course. After 12 months the cumulative recovery rate flattened. To prevent and manage chronicity, timely treatment, and chronic disease management are required. The risk indicators found may help to identify individuals with an anxiety disorder at risk for chronicity.

Specific Phobia: Risk Factor of Other Psychiatric Disorders.

ABSTRACT: Predicting the onset and persistence of psychopathology and limited functioning might enable personalized care. Specific phobia (SP) might serve as a predictor, but this needs further evaluation. Participants of the Netherlands Mental Health Survey and Incidence Study-2 were divided into three groups: no-SP (n = 6094), history of SP (n = 204), and current SP (n = 348). Results showed that current SP was associated with a higher prevalence of other anxiety disorders, mood and substance use disorders, and lower levels of functioning. The 6-year onset of other anxiety disorders was associated with history and current SP. Current-SP was also associated with the onset of mood disorders. Neuroticism and childhood trauma only partly accounted for these associations. To conclude, SP was independently associated with presence and onset of other disorders and with limited functioning over time. The presence of SP may serve as an identifier of persons vulnerable to the development of other psychopathologies.

Course trajectories of anxiety disorders: Results from a 6-year follow-up in a general population study.

OBJECTIVE: Little is known about the course of anxiety disorders in the general population. This study provides insights into the course of anxiety disorders in the general population taking into account transition to residual symptoms and to other diagnostic categories. METHODS: Using data from three waves of the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2; n = 6646), subjects with anxiety disorders (T0;n = 243) were divided into three mutually exclusive course trajectories according to their diagnostic status at 3-year (T1) and 6-year (T2) follow-up: remission group (no disorder at T2), intermittent course group (no disorder at T1 and disorder at T2) and chronic course group (disorder at all measurements). Transition to residual symptoms or other psychopathology were studied. In addition, predictors of course trajectories were assessed. RESULTS: During 6-year follow-up, 77.8% of subjects achieved remission, 14.0% followed an intermittent course and 8.2% a chronic course. Of those in remission, residual anxiety symptoms remained in 46.6%, while 7.9% developed another disorder between T0 and T2. Compared with the remitting group, a chronic course was predicted by not living with a partner, multiple negative life events, neuroticism, lower mental functioning, severity of anxiety symptoms, use of mental health care and medication use. LIMITATIONS: The intermittent and chronic course groups were small, limiting statistical power. As a result, certain predictors may not have reached significance. CONCLUSIONS: In the general population at 6-year follow-up, 77.8% of subjects with anxiety disorders achieved remission. Because of transition to residual symptoms or another diagnostic category, only 52.4% of those subjects had a true favourable outcome.

Long-term disability in major depressive disorder: a 6-year follow-up study.

BACKGROUND: Major depressive disorder (MDD) represents a leading cause of disability. This study examines the course of disability in patients with chronic, recurrent and remitting MDD compared to healthy controls and identifies predictors of disability in remitting MDD. METHODS: We included 914 participants from the Netherlands Study of Depression and Anxiety (NESDA). DSM-IV MDD and WHO DAS II disability were assessed at baseline and at 2, 4 and 6 years. Six-year total and domain-specific disability were analysed and compared in participants with chronic (n = 57), recurrent (n = 120), remitting (n = 127) MDD and in healthy controls (n = 430). Predictors of residual disability were identified using linear regression analysis. RESULTS: At baseline, most disability was found in chronic MDD, followed by recurrent MDD, remitting MDD and healthy controls. Across diagnostic groups, most disability was found in household activities, interpersonal functioning, participation in society and cognition. A chronic course was associated with chronic disability. Symptom remission was associated with a decrease in disability, but some disability remained. In remitting MDD, higher residual disability was predicted by older age, more severe avoidance symptoms, higher disability at baseline and late symptom remission. Severity of residual disability correlated with the severity of residual depressive symptoms. CONCLUSIONS: Symptomatic remission is a prerequisite for improvements in disability. However, disability persists despite symptom remission. Therefore, treatment of MDD should include an explicit focus on disability, especially on the more complex domains. To this end, treatments should promote behavioural activation and address subthreshold depressive symptoms in patients with remitted MDD.

Toward identifying reproducible brain signatures of obsessive-compulsive profiles: rationale and methods for a new global initiative.

BACKGROUND: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. METHODS: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. DISCUSSION: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

A clinical staging approach to improving diagnostics in anxiety disorders: Is it the way to go?

BACKGROUND: Clinical staging is a paradigm in which stages of disease progression are identified; these, in turn, have prognostic value. A staging model that enables the prediction of long-term course in anxiety disorders is currently unavailable but much needed as course trajectories are highly heterogenic. This study therefore tailored a heuristic staging model to anxiety disorders and assessed its validity. METHODS: A clinical staging model was tailored to anxiety disorders, distinguishing nine stages of disease progression varying from subclinical stages (0, 1A, 1B) to clinical stages (2A-4B). At-risk subjects and subjects with anxiety disorders (n = 2352) from the longitudinal Netherlands Study of Depression and Anxiety were assigned to these nine stages. The model's validity was assessed by comparing baseline (construct validity) and 2-year, 4-year and 6-year follow-up (predictive validity) differences in anxiety severity measures across stages. Differences in depression severity and disability were assessed as secondary outcome measures. RESULTS: Results showed that the anxiety disorder staging model has construct and predictive validity. At baseline, differences in anxiety severity, social avoidance behaviors, agoraphobic avoidance behaviors, worrying, depressive symptoms and levels of disability existed across all stages (all p-values < 0.001). Over time, these differences between stages remained present until the 6-year follow-up. Differences across stages followed a linear trend in all analyses: higher stages were characterized by the worst outcomes. Regarding the stages, subjects with psychiatric comorbidity (stages 2B, 3B, 4B) showed a deteriorated course compared with those without comorbidity (stages 2A, 3A, 4A). CONCLUSION: A clinical staging tool would be useful in clinical practice to predict disease course in anxiety disorders.

Four-year course of quality of life and obsessive-compulsive disorder.

OBJECTIVE: Patients with obsessive compulsive disorder (OCD) have high disease burden. It is important to restore quality of life (QoL) in treatment, so that patients become able to live a fulfilling life. Little is known about the longitudinal course of QoL in patients with OCD, its association with remission from OCD, and about factors that contribute to an unfavourable course of QoL in remitting patients. METHODS: Study on the 4-year course of QoL of patients with chronic (n = 144), intermittent (n = 22), and remitting OCD (n = 73) using longitudinal data of the Netherlands Obsessive Compulsive Disorder Association (NOCDA; complete data: n = 239; imputed data n = 382). The EuroQol five-dimensional questionnaire (EQ-5D) utility score was used to assess QoL. In patients with remitting OCD, we examined patient characteristics that contributed to an unfavourable course of QoL, including sociodemographics, OCD characteristics, psychiatric comorbidity, and personality traits. RESULTS: Course of QoL was associated with course of OCD. QoL improved in those who remitted from OCD; however, even in these patients, QoL remained significantly below the population norms. The correlation between QoL and severity of OCD was only moderate: r = - 0.40 indicating that other factors besides OCD severity contribute to QoL. In remitters, more severe anxiety and depression symptoms were related to a lower QoL. Results were similar in complete and imputed data sets. CONCLUSIONS: Remission from OCD is associated with improvement of QoL, but comorbid anxiety and depression symptoms hamper the improvement of QoL. QoL could be improved by reducing OCD symptoms in patients with OCD and by treating comorbid anxiety and depression symptoms in remitting patients.

Aligning the many definitions of treatment resistance in anxiety disorders: A systematic review.

Anxiety Disorders often show a chronic course, even when treated with one of the various effective treatments available. Lack of treatment effect could be due to Treatment Resistance (TR). Consensus on a definition for TR Anxiety Disorders (TR-AD) is highly needed as currently many different operationalizations are in use. Therefore, generalizability in current TR-AD research is suboptimal, hampering improvement of clinical care. The objective of this review is to evaluate the currently used definitions of TR-AD by performing a systematic review of available literature. Out of a total of n = 13 042, 62 studies that operationalized TR-AD were included. The current review confirms a lack of consensus on TR-AD criteria. In 62.9% of the definitions, TR was deemed present after the first treatment failure. Most studies (93.0%) required pharmacological treatment failures, whereas few (29.0%) required psychological treatment failures. However, criteria for what constitutes "treatment failure" were not provided in the majority of studies (58.1%). Definitions for minimal treatment duration ranged from at least 4 weeks to at least 6 months. Almost half of the TR-AD definitions (46.8%) required elevated anxiety severity levels in TR-AD. After synthesis of the results, the consensus definition considers TR-AD present after both at least one first-line pharmacological and one psychological treatment failure, provided for an adequate duration (at least 8 weeks) with anxiety severity remaining above a specified threshold. This definition could contribute to improving course prediction and identifying more targeted treatment options for the highly burdened subgroup of TR-AD patients.

The GET READY relapse prevention programme for anxiety and depression: a mixed-methods study protocol.

BACKGROUND: Since anxiety and depressive disorders often recur, self-management competencies are crucial for improving the long-term course of anxiety and depressive disorders. However, few relapse prevention programmes are available that focus on improving self-management. E-health combined with personal contact with a mental health professional in general practice might be a promising approach for relapse prevention. In this protocol, the GET READY (Guided E-healTh for RElapse prevention in Anxiety and Depression) study will be described in which a relapse prevention programme is developed, implemented and evaluated. The aim of the study is to determine patients' usage of the programme and the associated course of their symptoms, to examine barriers and facilitators of implementation, and to assess patients' satisfaction with the programme. METHODS: Participants are discharged from mental healthcare services, and are in complete or partial remission. They receive access to an E-health platform, combined with regular contact with a mental health professional in general practices. Online questionnaires will be completed at baseline and after 3, 6 and 9 months. Also, semi-structured qualitative individual interviews and focus group interviews will be conducted with patients and mental health professionals. DISCUSSION: This mixed-methods observational cohort study will provide insights into the use of a relapse prevention programme in relation to the occurrence of symptoms, as well as in its implementation and evaluation. Using the results of this study, the relapse prevention programme can be adapted in accordance with the needs of patients and mental health professionals. If this programme is shown to be acceptable, a randomized controlled trial may be conducted to test its efficacy. TRIAL REGISTRATION: Retrospectively registered in the Netherlands Trial Register ( NTR7574 ; 25 October 2018).

Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial.

BACKGROUND: Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response. METHODS/DESIGN: This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months' follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored. DISCUSSION: This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia. TRIAL REGISTRATION: Netherlands Trial Register NTR5100 . Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7.

The impact of depression and anxiety treatment on biological aging and metabolic stress: study protocol of the MOod treatment with antidepressants or running (MOTAR) study.

BACKGROUND: Depressive and anxiety disorders have shown to be associated to premature or advanced biological aging and consequently to adversely impact somatic health. Treatments with antidepressant medication or running therapy are both found to be effective for many but not all patients with mood and anxiety disorders. These interventions may, however, work through different pathophysiological mechanisms and could differ in their impact on biological aging and somatic health. This study protocol describes the design of an unique intervention study that examines whether both treatments are similarly effective in reducing or reversing biological aging (primary outcome), psychiatric status, metabolic stress and neurobiological indicators (secondary outcomes). METHODS: The MOod Treatment with Antidepressants or Running (MOTAR) study will recruit a total of 160 patients with a current major depressive and/or anxiety disorder in a mental health care setting. Patients will receive a 16-week treatment with either antidepressant medication or running therapy (3 times/week). Patients will undergo the treatment of their preference and a subsample will be randomized (1:1) to overcome preference bias. An additional no-disease-no-treatment group of 60 healthy controls without lifetime psychopathology, will be included as comparison group for primary and secondary outcomes at baseline. Assessments are done at week 0 for patients and controls, and at week 16 and week 52 for patients only, including written questionnaires, a psychiatric and medical examination, blood, urine and saliva collection and a cycle ergometer test, to gather information about biological aging (telomere length and telomerase activity), mental health (depression and anxiety disorder characteristics), general fitness, metabolic stress-related biomarkers (inflammation, metabolic syndrome, cortisol) and genetic determinants. In addition, neurobiological alterations in brain processes will be assessed using structural and functional Magnetic Resonance Imaging (MRI) in a subsample of at least 25 patients per treatment arm and in all controls. DISCUSSION: This intervention study aims to provide a better understanding of the impact of antidepressant medication and running therapy on biological aging, metabolic stress and neurobiological indicators in patients with depressive and anxiety disorders in order to guide a more personalized medicine treatment. TRIAL REGISTRATION: Trialregister.nl Number of identification: NTR3460, May 2012.

Failure to Respond after Reinstatement of Antidepressant Medication: A Systematic Review.

BACKGROUND: Following remission of an anxiety disorder or a depressive disorder, antidepressants are frequently discontinued and in the case of symptom occurrence reinstated. Reinstatement of antidepressants seems less effective in some patients, but an overview is lacking. This systematic review aimed to provide insight into the magnitude and risk factors of response failure after reinstatement of antidepressants in patients with anxiety disorders, depressive disorders, obsessive-compulsive disorder (OCD), or posttraumatic stress disorder (PTSD). METHOD: PubMed, Embase, and trial registers were systematically searched for studies in which patients: (1) had an anxiety disorder, a depressive disorder, OCD, or PTSD and (2) experienced failure to respond after reinstatement of a previously effective antidepressant. RESULTS: Ten studies reported failure to respond following antidepressant reinstatement. The phenomenon was observed in 16.5% of patients with a depressive disorder, OCD, and social phobia and occurred in all common classes of antidepressants. The range of response failure was broad, varying between 3.8 and 42.9% across studies. No risk factors for failure to respond were investigated. The overall study quality was limited. CONCLUSION: Research investigating response failure is scarce and the study quality limited. Response failure occurred in a substantial minority of patients. Contributors to the relevance of this phenomenon are the prevalence of the investigated disorders, the number of patients being treated with antidepressants, and the occurrence of response failure for all common classes of antidepressants. This systematic review highlights the need for studies systematically investigating this phenomenon and associated risk factors.

Presence and Predictive Value of Obsessive-Compulsive Symptoms in Anxiety and Depressive Disorders.

OBJECTIVE: Obsessive-compulsive symptoms (OCS) co-occur frequently with anxiety and depressive disorders, but the nature of their relationship and their impact on severity of anxiety and depressive disorders is poorly understood. In a large sample of patients with anxiety and depressive disorders, we assessed the frequency of OCS, defined as a Young Adult Self-Report Scale-obsessive-compulsive symptoms score >7. The associations between OCS and severity of anxiety and/or depressive disorders were examined, and it was investigated whether OCS predict onset, relapse, and persistence of anxiety and depressive disorders. METHODS: Data were obtained from the third (at 2-year follow-up) and fourth wave (at 4-year follow-up) of data collection in the Netherlands Study of Anxiety and Depression cohort, including 469 healthy controls, 909 participants with a remitted disorder, and 747 participants with a current anxiety and/or depressive disorder. RESULTS: OCS were present in 23.6% of the total sample, most notably in those with current combined anxiety and depressive disorders. In patients with a current disorder, OCS were associated with severity of this disorder. Moreover, OCS predicted (1) first onset of anxiety and/or depressive disorders in healthy controls (odds ratio [OR], 5.79; 95% confidence interval [CI], 1.15 to 29.14), (2) relapse in those with remitted anxiety and/or depressive disorders (OR, 2.31; 95% CI, 1.55 to 3.46), and (3) persistence in patients with the combination of current anxiety and depressive disorders (OR, 4.42; 95% CI, 2.54 to 7.70) within the 2-year follow-up period Conclusions: OCS are closely related to both the presence and severity of anxiety and depressive disorders and affect their course trajectories. Hence, OCS might be regarded as a course specifier signaling unfavorable outcomes. This specifier may be useful in clinical care to adapt and intensify treatment in individual patients.