Viewpoint: Assessing the value of mental health treatments in Europe.

One in eight individuals worldwide lives with a mental health disorder. For many European countries, the prevalence is even higher, with one in four people reporting mental health problems [1]. Three-quarters of all mental health disorders develop before age 25, with many presenting initially in undiagnosed forms already in the mid-teens and eventually manifesting as severe disorders and lasting into old age [2]. There is also growing evidence that mental health disorder symptoms cross diagnoses and people frequently have more than one mental health disorder [3].

Economic impact of reducing treatment gaps in depression.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent across Europe. While evidence-based treatments exist, many people with MDD have their condition undetected and/or untreated. This study aimed to assess the cost-effectiveness of reducing treatment gaps using a modeling approach. METHODS: A decision-tree model covering a 27-month time horizon was used. This followed a care pathway where MDD could be detected or not, and where different forms of treatment could be provided. Expected costs pertaining to Germany, Hungary, Italy, Portugal, Sweden, and the UK were calculated and quality-adjusted life years (QALYs) were estimated. The incremental costs per QALY of reducing detection and treatment gaps were estimated. RESULTS: The expected costs with a detection gap of 69% and treatment gap of 50% were €1236 in Germany, €476 in Hungary, €1413 in Italy, €938 in Portugal, €2093 in Sweden, and €1496 in the UK. The incremental costs per QALY of reducing the detection gap to 50% ranged from €2429 in Hungary to €10,686 in Sweden. The figures for reducing the treatment gap to 25% ranged from €3146 in Hungary to €13,843 in Sweden. CONCLUSIONS: Reducing detection and treatment gaps, and maintaining current patterns of care, is likely to increase healthcare costs in the short term. However, outcomes are improved, and reducing these gaps to 50 and 25%, respectively, appears to be a cost-effective use of resources.

The effects of COVID-19 on European healthcare provision for working-age adults with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide, and yet delivery of care for this illness is rife with gaps. The COVID-19 pandemic has had far reaching implications for every facet of healthcare, and MDD is no exception. This scoping review aimed to ascertain the impacts of COVID-19 on the delivery of MDD care in Europe, as well as to evaluate any novel MDD care strategies trialled in this period. METHODS: We searched the PubMed and PsycINFO databases up to January 2022 with a strategy centred around COVID-19 and MDD. Full texts of eligible studies examining working-age adults and conducted in Europe were evaluated against several criteria. All outcomes were then extracted and a narrative synthesis was constructed to summarise identified themes. RESULTS: Of 1,744 records identified in our search, 11 articles were eligible for inclusion in the review. In general, these studies reported a decrease in treatment rates, access to care, and perceived access to care during the COVID-19 pandemic. In addition, digital interventions trialled during the pandemic were broadly well-received by users, though their efficacy in improving MDD care was ambiguous. CONCLUSIONS: Despite a limited number of pertinent studies, this scoping review identified a trend of exacerbated treatment gaps in MDD care during the pandemic. Several of our pre-specified gaps, including delays to detection or treatment of depression and rates of follow-up contacts, remained unexplored in the context of COVID-19. This highlights the need for further investigation to obtain a full understanding of the relationship between COVID-19 and MDD care in Europe.

Value of schizophrenia treatment II: Decision modelling for developing early detection and early intervention services in the Czech Republic.

BACKGROUND: Positive findings on early detection and early intervention services have been consistently reported from many different countries. The aim of this study, conducted within the European Brain Council project "The Value of Treatment", was to estimate costs and the potential cost- savings associated with adopting these services within the context of the Czech mental health care reform. METHODS: Czech epidemiological data, probabilities derived from meta-analyses, and data on costs of mental health services in the Czech Republic were used to populate a decision analytical model. From the health care and societal perspectives, costs associated with health care services and productivity lost were taken into account. One-way sensitivity analyses were conducted to explore the uncertainty around the key parameters. RESULTS: It was estimated that annual costs associated with care as usual for people with the first episode of psychosis were as high as 46 million Euro in the Czech Republic 2016. These annual costs could be reduced by 25% if ED services were adopted, 33% if EI services were adopted, and 40% if both, ED and EI services, were adopted in the country. Cost-savings would be generated due to decreased hospitalisations and better employment outcomes in people with psychoses. CONCLUSIONS: Adopting early detection and early intervention services in mental health systems based on psychiatric hospitals and with limited access to acute and community care could generate considerable cost- savings. Although the results of this modelling study needs to be taken with caution, early detection and early intervention services are recommended for multi-centre pilot testing accompanied by full economic evaluation in the region of Central and Eastern Europe.

Value of schizophrenia treatment I: The patient journey.

BACKGROUND: The aim of the European Brain Council project "The Value of Treatment" was to provide evidence-based, cost-effective policy recommendations for a patient-centered and sustainable coordinated care model for brain disorders. The first part of schizophrenia study examined the needs and gaps in the patients' care pathway. METHODS: Descriptive analysis was based on an inventory of needs and treatment opportunities, using focus group sessions, expert interviews, users' input, and literature review. Three patient pathways were selected: indicated prevention, duration of untreated psychosis, and relapse prevention. RESULTS: The analysis identified several critical barriers to optimal treatment. Available health care services often miss or delay detection of symptoms and diagnosis in at-risk individuals. There is a lack of illness awareness among patients, families, and the public; scarcity of information, training and education among primary care providers; stigmatizing beliefs. Early symptom recognition and timely intervention result in better outcome and prognosis; effective management leads to a functional recovery. In the current model of care, there is insufficient cooperation between health and social care providers, patients and families, inadequate utilization of pharmacological and psychosocial interventions, lacking patient monitoring, and low implementation of integrated community care. CONCLUSIONS: Early detection and early intervention programs, timely intervention, and relapse prevention are essential for effective management of schizophrenia. It requires a paradigm shift from symptom control, achieving and maintaining remission, to the emphasis on recovery. Since the current services are not able to accomplish this goal, changes in mental health policies are needed.

Antidepressant effect in older depressed patients: the lessons of two agomelatine trials.

The present paper reports in parallel the findings of the two phase III trials that evaluated the efficacy of agomelatine in older depressed patients. It describes how the particular methodological innovations (particularly in relation to patient selection, design and accuracy of diagnosis of depression) introduced in study 2 have improved the quality of recruitment of patients and the assay sensitivity. Study 1 lacked assay sensitivity, and among the many differences with study 2, the inclusion of unexpected mildly ill patients could have inflated the placebo response. The increased demands on investigators in study 2 appear to have reduced the placebo effect and showed a robust benefit of agomelatine. The two agomelatine studies offer the opportunity to discuss hypotheses that have been raised to explain the low level of response of older patients to available antidepressants.

Efficacy of Desvenlafaxine 50 mg/d Versus Placebo in the Long-Term Treatment of Major Depressive Disorder: A Randomized, Double-Blind Trial.

OBJECTIVE: To examine long-term (11-month) antidepressant efficacy of desvenlafaxine 50 mg/d across a broad range of clinical and functional outcomes in patients with major depressive disorder. METHOD: Adult outpatients (≥ 18 years) with major depressive disorder (DSM-IV criteria) and a 17-item Hamilton Depression Rating Scale (HDRS-17) total score ≥ 20 at screening and baseline who responded to 8 weeks of open-label desvenlafaxine 50 mg/d and had a continuing stable response through week 20 were randomly assigned to receive placebo or desvenlafaxine 50 mg/d in a 6-month, double-blind, randomized withdrawal period. Depressive symptoms were evaluated using the HDRS-17, 6-item HDRS, and Clinical Global Impressions-Severity of Ilness and -Improvement (CGI-S, CGI-I). Health outcomes included the Work Productivity and Activity Impairment (WPAI) questionnaire and the World Health Organization 5-Item Well-Being Index (WHO-5). The trial was conducted from June 2009 to March 2011 at 87 study sites in 14 countries worldwide. RESULTS: Of 874 patients enrolled in open-label treatment, 548 patients were randomly assigned to receive double-blind placebo (n = 276) or desvenlafaxine 50 mg/d (n = 272). At the end of the 6-month double-blind treatment, improvements in depressive symptoms were better maintained among the desvenlafaxine- than placebo-treated patients on all efficacy endpoints (all P ≤ .001); in the desvenlafaxine group, 21.8% (vs 42.9% in the placebo group) had CGI-I ratings of 5, 6, and 7 (minimally worse/much worse/very much worse), and 74.4% met criteria for remission (placebo: 54.2%). WPAI and WHO-5 scores indicated significantly better productivity and well-being with continued desvenlafaxine (vs placebo, P ≤ .001). CONCLUSIONS: Long-term treatment with desvenlafaxine 50 mg/d maintained improvements in major depressive disorder among adult outpatients who exhibited a stable therapeutic response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00887224.

Structural hippocampal anomalies in a schizophrenia population correlate with navigation performance on a wayfinding task.

Episodic memory, related to the hippocampus, has been found to be impaired in schizophrenia. Further, hippocampal anomalies have also been observed in schizophrenia. This study investigated whether average hippocampal gray matter (GM) would differentiate performance on a hippocampus-dependent memory task in patients with schizophrenia and healthy controls. Twenty-one patients with schizophrenia and 22 control participants were scanned with an MRI while being tested on a wayfinding task in a virtual town (e.g., find the grocery store from the school). Regressions were performed for both groups individually and together using GM and performance on the wayfinding task. Results indicate that controls successfully completed the task more often than patients, took less time, and made fewer errors. Additionally, controls had significantly more hippocampal GM than patients. Poor performance was associated with a GM decrease in the right hippocampus for both groups. Within group regressions found an association between right hippocampi GM and performance in controls and an association between the left hippocampi GM and performance in patients. A second analysis revealed that different anatomical GM regions, known to be associated with the hippocampus, such as the parahippocampal cortex, amygdala, medial, and orbital prefrontal cortices, covaried with the hippocampus in the control group. Interestingly, the cuneus and cingulate gyrus also covaried with the hippocampus in the patient group but the orbital frontal cortex did not, supporting the hypothesis of impaired connectivity between the hippocampus and the frontal cortex in schizophrenia. These results present important implications for creating intervention programs aimed at measuring functional and structural changes in the hippocampus in schizophrenia.

The efficacy of agomelatine in elderly patients with recurrent major depressive disorder: a placebo-controlled study.

OBJECTIVE: The present placebo-controlled study evaluated the efficacy, tolerability, and safety of 8-week treatment with agomelatine (25-50 mg/d by mouth) in elderly patients with major depressive disorder (MDD). METHOD: Elderly outpatients aged ≥ 65 years with a primary diagnosis of moderate to severe episode of recurrent MDD (DSM-IV-TR) were recruited in 27 clinical centers in Argentina, Finland, Mexico, Portugal, and Romania from November 2009 to October 2011. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS17) total score. RESULTS: A total of 222 elderly patients entered the study (151 in the agomelatine group, 71 in the placebo group), including 69 patients aged 75 years and older. Agomelatine improved depressive symptoms in the elderly population, as evaluated by the HDRS17 total score, in terms of last postbaseline value (agomelatine-placebo difference: mean estimate [standard error] = 2.67 [1.06] points; P = .013) and response to treatment (agomelatine, 59.5%; placebo, 38.6%; P = .004). The agomelatine-placebo difference according to the Clinical Global Impressions-Severity of Illness scale (CGI-S) score was 0.48 (0.19). The agomelatine-placebo difference (estimate [standard error]) for remission on the HDRS17 was 6.9% (4.7%) and did not achieve statistical significance (P = .179, post hoc analysis). Clinically relevant effects of agomelatine were confirmed on all end points in the subset of severely depressed patients (HDRS17 total score ≥ 25 and CGI-S score ≥ 5 at baseline). Agomelatine was well tolerated by patients, with only minimal distinctions from placebo. CONCLUSIONS: The present study provides the first evidence that an 8-week treatment with agomelatine 25-50 mg/d efficiently relieves depressive symptoms and is well tolerated in elderly depressed patients older than 65 years. TRIAL REGISTRATION: Controlled-Trials.com identifier: ISRCTN57507360.

Efficacy and safety of desvenlafaxine 50 mg/d for prevention of relapse in major depressive disorder:a randomized controlled trial.

OBJECTIVE: To evaluate the long-term (11-month) efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) at the recommended 50-mg/d dose in preventing relapse in patients with major depressive disorder (MDD). METHOD: Adult outpatients (age ≥ 18 years) with MDD (DSM-IV criteria) and a 17-item Hamilton Depression Rating Scale (HDRS17) total score ≥ 20 at screening and baseline were enrolled in a multicenter, double-blind, placebo-controlled, randomized withdrawal trial conducted between June 2009 and March 2011. Patients who responded to 8-week open-label treatment with desvenlafaxine 50 mg/d with continuing stable response through week 20 were randomly assigned to receive placebo or desvenlafaxine 50 mg/d in a 6-month, double-blind, randomized withdrawal period. The primary efficacy endpoint was time to relapse following randomization to double-blind treatment, which was compared between groups using the log-rank test. Relapse was defined as HDRS17 total score ≥ 16, discontinuation for unsatisfactory response, hospitalization for depression, suicide attempt, or suicide. Safety and tolerability data were collected throughout the trial. RESULTS: A total of 874 patients were enrolled; 548 patients were randomly assigned to receive placebo (n = 276) or desvenlafaxine 50 mg/d (n = 272) in the double-blind withdrawal period. Time to relapse was significantly shorter for placebo versus desvenlafaxine (P < .001). At the end of the 6-month double-blind treatment, the estimated probability of relapse was 30.2% for placebo versus 14.3% for desvenlafaxine 50 mg/d. Safety and tolerability results were generally consistent with those in short-term studies of desvenlafaxine 50 mg/d. CONCLUSIONS: Desvenlafaxine at the recommended dose of 50 mg/d was effective in relapse prevention of depression during a 6-month period in patients who demonstrated stable response after 20 weeks of open-label desvenlafaxine treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00887224.

Decreased fMRI activity in the hippocampus of patients with schizophrenia compared to healthy control participants, tested on a wayfinding task in a virtual town.

Intact episodic memory requires the ability to make associations between the contextual features of an event, referred to as contextual binding. Binding processes combine different contextual elements into a complete memory representation. It has been proposed that binding errors during the encoding process are responsible for the episodic memory impairments reported in schizophrenia. Since the hippocampus is critical for contextual binding and episodic memory, it was hypothesized that patients with schizophrenia would show a deficit in information processing in the hippocampus, measured with functional magnetic resonance imaging (fMRI). In the current experiment, 21 patients with schizophrenia and 22 healthy control participants were scanned while being tested on navigating in a virtual town (i.e. find the grocery store from the school), a task that was shown to be critically dependent on the hippocampus. Between-group comparisons revealed significantly less activation among patients relative to controls in the left middle frontal gyrus, and right and left hippocampi. We propose that the context and the content are not appropriately linked, therefore affecting the formation of a cognitive map representation in the patient group and eliciting a contextual binding deficit.

Is it time to shift to better characterization of patients in trials assessing novel antidepressants? An example of two relapse prevention studies with agomelatine.

The present paper reports in parallel the findings of the two studies that evaluated the efficacy of agomelatine in preventing relapse of depression. It describes the methodological adjustments made between the first and the second trial, particularly in relation to patient selection and accuracy of diagnosis of depression. Patients with major depressive disorder who responded to an 8/10-week course of agomelatine 25-50 mg treatment were randomly assigned to receive continuation treatment with agomelatine or placebo during a 24-week, randomized, double-blind treatment period with an optional 18- or 20-week double-blind extension period. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. Study 1 lacked assay sensitivity because of an unexpectedly low relapse rate in the placebo arm, but was instructive in showing that the agomelatine effect was better than placebo only in those patients with higher symptom levels at baseline. Study 2 showed a robust benefit of agomelatine - a two-fold reduction in the relapse rate - observed at least up to 10 months in both the overall population and the more severely depressed patients. The methodological adjustments introduced in study 2 (e.g. a minimum subscore calculated from eight specific Hamilton Depression Rating Scale items, the use of the self-rating questionnaire Hospital Anxiety Depression Scale and the Sheehan questionnaire) have assured an adequate severity of depression not only on the basis of ratings of symptom severity but also on measures of functional impairment. We did not find increased severity of symptoms in study 2, but we hypothesize that the increased demands on investigators improved the quality of recruitment to represent more real-world patients. Adopting these innovations could contribute towards lower failure rates for future placebo-controlled clinical trials in the field.

The organization of psychiatric care in France: current aspects and future challenges.

In the last four decades, psychiatric care in France has led to the development of catchment area-based service provision. Within each geographical area teams are now responsible for psychiatric care both at outpatient and inpatient levels. However, financial and economic constraints have led to a reduction in beds and staffing levels. The numbers of psychiatrists in private practice has remained more or less the same over the years due to steady demand and other factors. As in many other western European countries, de-institutionalization has been a major driver in the evolution of psychiatric care delivery in France. This is linked with several developments, including the introduction of more efficient pharmaceutical drugs which have reduced the likelihood of relapse. Other factors which have influenced this include the progressive 'de-stigmatization' of psychiatric disorders and policy changes leading to significant bed reduction. All of these factors are inter-linked and have influenced psychiatric care delivery. In this paper we provide an overview of the current state of psychiatric care and its delivery in France.

Wayfinding: the effects of large displays and 3-D perception.

Large displays and stereopsis have been shown to improve performance in several virtual navigation tasks. In the present research, we sought to determine whether wayfinding could benefit from these factors. Participants were tested in a virtual town. There were three viewing conditions: a desktop, a large screen, and a large screen on which the virtual environment was viewed in three dimensions (3-D) using polarized glasses. Participants explored the town and had to remember the location of several landmarks. Their memory of the layout of the town was tested by asking them to navigate from one landmark to another, taking the shortest route possible. All groups performed equally well in terms of the distance traveled to target locations. From this result, we concluded that large displays and 3-D perception do not significantly contribute to wayfinding. Thus, experimental paradigms and training programs that utilize wayfinding are as valuable when administered on standard desktops as on more sophisticated and costly equipment and do not induce simulator sickness as large displays tend to do.

Common and distinct neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: a voxel-based meta-analysis of functional magnetic resonance imaging studies.

Neuroimaging studies have consistently shown functional brain abnormalities in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD). However, the extent to which these two disorders are associated with similar or distinct neural changes remains unclear. We conducted a systematic review of functional magnetic resonance imaging studies comparing BD and MDD patients to healthy participants using facial affect processing paradigms. Relevant spatial coordinates from twenty original studies were subjected to quantitative Activation Likelihood Estimation meta-analyses based on 168 BD and 189 MDD patients and 344 healthy controls. We identified common and distinct patterns of neural engagement for BD and MDD within the facial affect processing network. Both disorders were associated with increased engagement of limbic regions. Diagnosis-specific differences were observed in cortical, thalamic and striatal regions. Decreased ventrolateral prefrontal cortical engagement was associated with BD while relative hypoactivation of the sensorimotor cortices was seen in MDD. Increased responsiveness in the thalamus and basal ganglia were associated with BD. These findings were modulated by stimulus valence. These data suggest that whereas limbic overactivation is reported consistently in patients with mood disorders, future research should consider the relevance of a wider network of regions in formulating conceptual models of BD and MDD.