Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: II. Sensitivity to treatment effects.

OBJECTIVE: Characteristics of difficult-to-treat depression (DTD), including infrequent symptom remission and poor durability of benefit, compel reconsideration of the outcome metrics historically used to gauge the effectiveness of antidepressant interventions. METHODS: Self-report and clinician assessments of depression symptom severity were obtained regularly over a 2-year period in a difficult-to-treat depression registry sample receiving treatment as usual (TAU), with or without vagus nerve stimulation (VNS). Alternative outcome metrics for characterizing symptom change were compared in effect size and discriminating power in distinguishing the vagus nerve stimulation + treatment as usual and treatment as usual treatment groups. We expected metrics based on remission status to produce weaker between-group separation than those based on the classifications of partial response or response and metrics that integrate information over time to produce greater separation than those based on single endpoint assessment. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination in separating the treatment groups than metrics based on partial response or response classifications. Metrics that integrated information over the 2-year observation period had stronger performance characteristics than those based on symptom scores at single endpoint assessment. For both the clinician-rated and self-report depression ratings, the metrics with the strongest performance characteristics were the median percentage change in symptom scores over the observation period and the proportion of the observation period in partial response or better. CONCLUSION: In difficult-to-treat depression, integrative symptom severity-based and time-based measures are sensitive and informative outcomes for assessing between-group treatment effects, while metrics based on remission status are not.

Vagus Nerve Stimulation as an Alternative to Maintenance Electroconvulsive Therapy for Difficult-to-Treat Depression.

ABSTRACT: Vagus nerve stimulation (VNS), an implantable neurostimulator, provides a valuable long-term treatment option for patients with difficult-to-treat depression. It has been reported that previous response to electroconvulsive therapy (ECT) might predict a better response to VNS and that VNS could reduce or eliminate the need for maintenance ECT in some patients. We present the case of a patient who received a total of more than 120 sessions of ECT over the course of 13 years because of a major depressive disorder, with favorable response but without achieving full remission. After implantation of VNS, ECT was discontinued, and her depressive symptoms improved, achieving remission within 12 months. This case supports VNS as an alternative to maintenance ECT in patients with difficult-to-treat depression who have shown previous response to ECT treatment.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: I. Association with change in quality of life.

BACKGROUND: In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. METHODS: Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores. CONCLUSIONS: Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

A longitudinal investigation of non-suicidal self-injury persistence patterns, risk factors, and clinical outcomes during the college period.

BACKGROUND: Although non-suicidal self-injury (NSSI) is known typically to begin in adolescence, longitudinal information is lacking about patterns, predictors, and clinical outcomes of NSSI persistence among emerging adults. The present study was designed to (1) estimate NSSI persistence during the college period, (2) identify risk factors and high-risk students for NSSI persistence patterns, and (3) evaluate the association with future mental disorders and suicidal thoughts and behaviors (STB). METHODS: Using prospective cohorts from the Leuven College Surveys (n = 5915), part of the World Mental Health International College Student Initiative, web-based surveys assessed mental health and psychosocial problems at college entrance and three annual follow-up assessments. RESULTS: Approximately one in five (20.4%) students reported lifetime NSSI at college entrance. NSSI persistence was estimated at 56.4%, with 15.6% reporting a high-frequency repetitive pattern (≥five times yearly). Many hypothesized risk factors were associated with repetitive NSSI persistence, with the most potent effects observed for pre-college NSSI characteristics. Multivariate models suggest that an intervention focusing on the 10-20% at the highest predicted risk could effectively reach 34.9-56.7% of students with high-frequency repetitive NSSI persistence (PPV = 81.8-93.4, AUC = 0.88-0.91). Repetitive NSSI persistence during the first two college years predicted 12-month mental disorders, role impairment, and STB during the third college year, including suicide attempts. CONCLUSIONS: Most emerging adults with a history of NSSI report persistent self-injury during their college years. Web-based screening may be a promising approach for detecting students at risk for a highly persistent NSSI pattern characterized by subsequent adverse outcomes.

Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

The temporal experience in depression: from slowing down and delayed help seeking to the emergency setting and length of treatment.

The present paper discusses the 'time' dimension in depression, from the phenomenological experience to the diagnostic criteria, from delayed help seeking to the emergency room, from a (non) timely follow-up to (non) adherence to treatment. The temporal experience is fundamentally disturbed in depression and recent neurophenomenological findings help in better understanding this dimension. The duration of symptoms needed to fulfil diagnostic criteria are somewhat arbitrary. Depression dramatically decreases life expectancy mainly through increased non-suicidal mortality. The time from help seeking to getting treatment (between delayed help seeking and the emergency room) is contradictory and the length of treatment (from too short to too long) suggests that taking better account of these phenomena could improve depression treatment.

The Effect of Electroconvulsive Therapy on Positive Affect and Hedonism in Patients With Depression: A Prospective Study.

OBJECTIVES: The outcome of antidepressant treatments is generally assessed with standardized symptom scales such as the Quick Inventory of Depressive Symptomatology-Clinician Rating (QIDS-C). These scales, however, might not reflect patients' expectations for treatment, including a recovery of positive affect (PA) and hedonism. The Leuven Affect and Pleasure Scale (LAPS) was developed to better reflect patients' expectations for treatment. We used the LAPS to investigate changes in PA and hedonism alongside depressive symptoms during electroconvulsive therapy (ECT) and over 12 weeks after treatment. METHODS: Fifty-three patients with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, depressive episode, referred for ECT, were included in this prospective study. The LAPS and QIDS-C were administered before and 1 and 12 weeks after the ECT course. LAPS normative levels were obtained in 149 healthy controls. RESULTS: Pearson correlations revealed only moderate overlap of the QIDS-C with PA and hedonism. Piecewise linear mixed models indicated significant improvements in depressive symptoms (QIDS-C and LAPS negative affect), PA, and hedonism during ECT. In the 12 weeks after ECT treatment, negative affect and QIDS-C further improved, but PA and hedonism plateaued. Exploratory analyses indicated that only fully remitted patients (QIDS-C) attained normative levels on PA and hedonism at 12 weeks after ECT. CONCLUSIONS: Standardized symptom scales (QIDS-C) may incompletely reflect clinical change in ECT treatment for depression. Although ECT improved depressive symptoms, PA, and hedonism in patients with depression, only fully remitted patients attained normative levels of PA and hedonism, due to plateaus in improvement. These plateaus were not observed for depressive symptoms, which further improved after ECT discontinuation.

Outcome in depression (II): beyond the Hamilton Depression Rating Scale.

BACKGROUND: The Leuven Affect and Pleasure Scale (LAPS) was developed as an outcome measure in major depressive disorder (MDD) tha treflects patient treatment expectations. The present report investigates whether the LAPS negative affect, the LAPS positive affect, and the LAPS hedonic tone have added value on top of the Hamilton Depression Rating Scale (HAMD) in explaining generic as well as patient-centered outcomes. METHODS: A total of 109 outpatients with Diagnostic and Statistical Manual of Mental Disorders, fifth edition, criteria for MDD were assessed over 8 weeks of antidepressant treatment. At baseline and after 2, 4, and 8 weeks, the LAPS, HAMD, Snaith-Hamilton Pleasure Scale (SHAPS), Positive and Negative Affect Scale (PANAS), and Sheehan Disability Scale were administered. The Clinical Global Impression of Improvement (CGI-I) and the Patient Global Impression of Improvement (PGI-I) were also administered at endpoint. RESULTS: Changes in LAPS negative affect, LAPS positive affect, and LAPS hedonic tone explain 14% of the additional variance in CGI-I, 21% in PGI-I, 37% in cognitive functioning, 32% in overall functioning, 31% in "my life is meaningful," and 45% in "I feel happy." Compared to standard scales (PANAS and SHAPS), the LAPS negative affect, LAPS positive affect, and LAPS hedonic tone differentiate better between different levels of CGI-I or PGI-I. CONCLUSIONS: The LAPS has added value (on top of the HAMD) in explaining changes in both generic outcomes (CGI-I/PGI-I) and patient-centered dimensions. The LAPS negative and positive affects and the LAPS hedonic tone differentiate CGI-I and PGI-I scores better than corresponding scales supposed to cover the same domains.

Outcome in depression (I): why symptomatic remission is not good enough.

BACKGROUND: The Leuven Affect and Pleasure Scale (LAPS) is a depression outcome measure aiming to better reflect patient treatment expectations. We investigated the evolution of the LAPS and some comparator scales during antidepressant treatment and compared scores of remitters with scores of healthy controls. METHODS: A total of 109 outpatients with Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) major depressive disorder were assessed over 8 weeks of antidepressant treatment. At baseline and after 2, 4, and 8 weeks, the LAPS as well as the Hamilton Depression Rating Scale (HAMD), the Snaith-Hamilton Pleasure Scale (SHAPS), the Positive and Negative Affect Scale (PANAS), and the Sheehan Disability Scale (SDS) were administered. Healthy controls consisted of 38 Italian adults and 111 Belgian students. RESULTS: Correlations between baseline positive and negative affect were only moderate (R between -0.20 and -0.41). LAPS positive affect and hedonic tone showed higher correlations with LAPS cognitive functioning, overall functioning, meaningfulness of life, and happiness than HAMD scores or PANAS negative affect. HAMD remission was associated with normal levels of LAPS negative affect but with significantly lower levels of LAPS positive affect, hedonic tone, cognitive functioning, overall functioning, meaningfulness of life, and happiness. The scores on the latter subscales only reached healthy control scores when the HAMD approached a score of 0 or 1. CONCLUSIONS: The standard definition of remission (HAMD cutoff of 7) is probably adequate for remitting negative mood, but not good enough for recovering positive mood, hedonic tone, functioning, or meaningfulness of life.

Binge eating and purging in first-year college students: Prevalence, psychiatric comorbidity, and academic performance.

BACKGROUND: Binge eating and purging behaviors (BPB) are common among college students, but evidence is scant on prevalence and associations of BPB with mental health problems and objective academic performance. This study aims to investigate: (a) 12-month prevalence of BPB among college first-year students, (b) comorbidity patterns of BPB with various mental health problems, and (c) the association of BPB with objective academic functioning. METHODS: Using data from the Leuven College Surveys (Belgium), as part of the World Mental Health Surveys International College Student initiative, we cross-sectionally assessed 12-month BPB and mental health problems among college first-year students (n = 4,889; response rate = 73.2%) at the beginning of the academic year. Objective measures of academic functioning (final grades, expressed in academic year percentage "AYP" [0-100%] and academic failure) were obtained from administrative records at the end of the academic year. RESULTS: Twelve-month prevalence of BPB was 7.6% (7.3%binge eating and 1.0%purging), with higher rates among females than males. Bivariate models showed an association between BPB and numerous mental health problems (ORs = 3.4-18.4). Multivariate models showed associations with non-suicidal self-injury, post-traumatic stress, internalizing/externalizing problems and suicidal ideation. After controlling for sociodemographic characteristics and comorbid mental health problems, BPB were still associated with lower AYP (-4.1 to -11.2% range) and elevated odds of academic year failure (ORs = 1.4-4.2). CONCLUSIONS: BPB (especially binge eating) are relatively common and associated with mental health problems, comparatively low academic performance, and higher risk of academic failure among college first-year students. Further study is needed to examine the causal dynamics underlying these associations.

Vagus nerve stimulation as adjunctive therapy in patients with difficult-to-treat depression (RESTORE-LIFE): study protocol design and rationale of a real-world post-market study.

BACKGROUND: Depressive illness is associated with significant adverse consequences for patients and their families, and for society. Clinical challenges are encountered in the management of patients suffering from depression whether they are designated difficult-to-treat or treatment-resistant. Prospective serial depression treatment trials have shown that less than 40% of patients with major depressive disorder remit with an initial pharmacotherapy trial, and a progressively smaller proportion of patients remit with each subsequent trial. For patients who suffer from difficult-to-treat depression (DTD), treatments should focus on patient-centred symptom control, patient functioning, and improving patient quality of life. Among the treatment options for patients with DTD is Vagus Nerve Stimulation (VNS) Therapy. VNS Therapy involves intermittent electrical stimulation of the left cervical vagus nerve and has been shown to be efficacious for long-term management of patients with DTD. METHODS: RESTORE-LIFE is a prospective, observational, multi-site, global post-market study intended to assess short-, mid-, and long-term effectiveness and efficiency outcomes in a 'real-world' setting among patients with DTD treated with adjunctive VNS Therapy. A minimum of 500 patients will be implanted with a VNS Therapy System at up to 80 global sites. Eligible patients will participate in a baseline visit between 1 and 6 weeks before device implant and will be followed for a minimum of 36 months and a maximum of 60 months. The diagnosis of depression and comorbid disorders will be determined using the Mini-International Neuropsychiatric Interview (MINI). The primary endpoint is response rate, defined as a decrease of ≥50% in Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to 12 months post-implant. DISCUSSION: A standardized approach in the management of DTD may not be appropriate for the treatment of such a complex heterogenous patient population. This study has been designed to evaluate whether VNS Therapy meaningfully improves and sustains clinical and depressive symptom outcomes in patients with DTD. This study will investigate the durability of VNS response in DTD and utility of VNS for long-term disease management of DTD. In addition, the study results will potentially clarify clinical, functional, and health economic questions in a real-world patient population with DTD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03320304. Registered 25 October 2017.

The blurred line between anxiety and depression: hesitations on comorbidity, thresholds and hierarchy.

The delineation of anxiety and depression as well as the relation between anxiety and depression are still subject of debate. Many patients suffering from depression also suffer from anxiety, and many patients with anxiety suffer or will suffer from depression. The co-occurrence or co-morbidity is higher than what could be expected based on their respective prevalences, and even pushed some authors to call it cothymia. This epidemiological and clinical reality results in many conceptual hesitations. We first will summarize how the different (versions of the) classification systems do not seem to have been successful in their attempts to delineate the blurred line between depression and anxiety, before questioning whether a dialogue with a more phenomenological or psychopathological approach could be helpful in understanding the articulation between both affective phenomena, as well as in bridging neurobiological research and clinical practice.

Anhedonia in Depressive Disorder: A Narrative Review.

Since the introduction of DSM-III anhedonia has become a core depressive criterion and is defined as the loss of interest or pleasure. Although the origin of the word goes back to the end of the 19th century and numerous anhedonic symptoms are described in classic texts on depression, this centrality in the diagnosis of depression is only recent. Anhedonia is best described as a symptom complex with unclear boundaries cutting across the tripartite model of the mind (affect, volition, and cognition). Popular concepts of anhedonia pertain to the pleasure cycle and positive affectivity. These concepts partially overlap and are often mixed up, but clearly stem from different theoretical backgrounds: the affective science of reward processing versus more general, dimensional modelling of affect. The former concept seems more suitable to understand anhedonic emotions, the latter more suitable to understand anhedonic mood or trait. This narrative review covers the history of "anhedonia," the different anhedonic phenomena, and psychopathological concepts. An attempt is made to go beyond a merely descriptive psychopathology. Neurobiological and psychological insights shed a light on how symptoms are made and interconnected; these insights possibly call for a new psychopathological language.

How to improve adherence to antidepressant treatments in patients with major depression: a psychoeducational consensus checklist.

Studies conducted in primary care as well as in psychiatric settings show that more than half of patients suffering from major depressive disorder (MDD) have poor adherence to antidepressants. Patients prematurely discontinue antidepressant therapy for various reasons, including patient-related (e.g., misperceptions about antidepressants, side-effects, and lack of tolerability), clinician-related (e.g., insufficient instruction received by clinicians about the medication, lack of shared decision-making, and follow-up care), as well as structural factors (e.g., access, cost, and stigma). The high rate of poor adherence to antidepressant treatments provides the impetus for identifying factors that are contributing to noncompliance in an individual patient, to implement a careful education about this phenomenon. As adherence to antidepressants is one of the major unmet needs in MDD treatment, being associated with negative outcomes, we sought to identify a series of priorities to be discussed with persons with MDD with the larger aim to improve treatment adherence. To do so, we analyzed a series of epidemiological findings and clinical reasons for this phenomenon, and then proceeded to define through a multi-step consensus a set of recommendations to be provided by psychiatrists and other practitioners at the time of the first (prescription) visit with patients. Herein, we report the results of this initiative.

The Impact of (the Concept of) Treatment-Resistant Depression: An Opinion Review.

Treatment-resistant depression refers to major depressive disorder, treatment of the disorder, and failure to obtain an "acceptable" outcome. Regarding the disorder, the heterogeneous concept of major depressive disorder and the multiple definitions of treatment-resistant depression, hesitating between a categorical and a more dimensional approach, as well as the divergence between diagnostic criteria and the items in the assessment scales are a source of confusion. Classifications do not take into account the dramatic influence of patient characteristics strongly impacting outcome, although these can be the cause of so-called pseudo-resistance. Outcome is the result of spontaneous evolution, nonspecific factors (including placebo), and active treatment factors. These should be differentiated to have a reliable estimation of the impact of different treatment modalities before we can asses treatment-resistant depression or before we can ascertain the (non)efficacy of treatments for treatment-resistant depression.The impact and burden of major depressive disorder and treatment-resistant depression are immense and go far beyond their economic cost. It is often forgotten that both are not only associated with increased suicidality but also with nonsuicidal mortality and that both can even result in requests for assisted dying. The caregiver burden and associated stigma are also too often overlooked despite that it has been suggested that they do influence (treatment) outcome.

Prediction of major depressive disorder onset in college students.

BACKGROUND: Major depressive disorder (MDD) in college students is associated with substantial burden. AIMS: To assess 1-year incidence of MDD among incoming freshmen and predictors of MDD-incidence in a representative sample of students. METHOD: Prospective cohort study of first-year college students (baseline: n = 2,519, 1-year follow-up: n = 958) RESULTS: The incidence of MDD within the first year of college was 6.9% (SE = 0.8). The most important individual-level predictors of onset were prior suicide plans and/or attempts (OR = 9.5). The strongest population-level baseline predictors were history of childhood-adolescent trauma, stressful experience in the past 12 months, parental psychopathology, and other 12-month mental disorder. Multivariate cross-validated prediction (cross-validated AUC = 0.73) suggest that 36.1% of incident MDD cases in a replication sample would occur among the 10% of students at highest predicted risk (24.5% predicted incidence in this highest-risk subgroup). CONCLUSIONS: Screening at college entrance is a promising strategy to identify students at risk of MDD onset, which may improve the development and deployment of targeted preventive interventions.

A comparison of DSM-5 and DSM-IV agoraphobia in the World Mental Health Surveys.

BACKGROUND: The Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM-5) definition of agoraphobia (AG) as an independent diagnostic entity makes it timely to re-examine the epidemiology of AG. Study objective was to present representative data on the characteristics of individuals who meet DSM-IV criteria for AG (AG without a history of panic disorder [PD] and PD with AG) but not DSM-5 criteria, DSM-5 but not DSM-IV criteria, or both sets of criteria. METHODS: Population-based surveys from the World Mental Health Survey Initiative including adult respondents (n = 136,357) from 27 countries across the world. The Composite International Diagnostic Interview was used to assess AG and other disorders. RESULTS: Lifetime and 12-month prevalence estimates of DSM-5 AG (1.5% and 1.0%) were comparable to DSM-IV (1.4% and 0.9%). Of respondents meeting criteria in either system, 57.1% met criteria in both, while 24.2% met criteria for DSM-5 only and 18.8% for DSM-IV only. Severe role impairment due to AG was reported by a lower proportion of respondents who met criteria only for DSM-IV AG (30.4%) than those with both DSM-5 and DSM-IV AG (44.0%; χ 21 = 4.7; P = 0.031). The proportion of cases with any comorbidity was lower among respondents who met criteria only for DSM-IV AG (78.7%) than those who met both sets (92.9%; χ 21 = 14.5; P < 0.001). CONCLUSIONS: This first large survey shows that, compared to the DSM-IV, the DSM-5 identifies a substantial group of new cases with AG, while the prevalence rate remains stable at 1.5%. Severity and comorbidity are higher in individuals meeting DSM-5 AG criteria compared with individuals meeting DSM-IV AG criteria only.

Is there enough "interest in and pleasure in" the concept of depression? The development of the Leuven Affect and Pleasure Scale (LAPS).

OBJECTIVE: Presence of negative mood (depressed mood) and anhedonia (lack of interest and pleasure) are considered core symptoms of depression, while absence of positive mood is not taken into account. It is therefore remarkable that the depression scales routinely used to assess changes during antidepressant treatment (Hamilton Depression Rating Scale [HDRS], Montgomery-Åsberg Depression Rating Scale [MADRS]) do not really take into account anhedonia. Several scales were developed to assess positive mood and hedonic tone, but they only partially cover the multidimensional concept. Therefore we developed a new 16-item questionnaire, the Leuven Affect and Pleasure Scale (LAPS), to assess negative affect, positive affect, and hedonic tone. METHODS: This first article on the LAPS questionnaire reports on the correlations between the different items, on the factor analysis, and on the differences found in 3 groups of subjects : healthy college students (N=138), depressed but still functioning college students (N=27), and severely depressed inpatients (N=38). These differences were calculated using univariate general linear models with Bonferroni post-hoc testing, and effect sizes were expressed in η2. RESULTS: Negative and positive affect were only moderately correlated, and the 4 independent variables (cognitive functioning, overall functioning, meaningful life, and happiness) had stronger correlations with positive affect than with negative affect. The major difference in negative affect was between healthy college students and depressed college students, positive affect was different between the 3 groups, and the major difference for hedonic tone was between depressed college students and depressed inpatients. Affiliative positive affect and the affiliative hedonic function were well preserved, even in depressed inpatients. CONCLUSIONS: This preliminary report suggests that the LAPS offers a comprehensive assessment of negative and positive affect, of hedonic tone, and of independent variables (cognitive functioning, overall functioning, meaningful life, and happiness). Clinically relevant differences in subscores were found in 3 groups of subjects with variable levels of depression (healthy subjects, mildly depressed subjects, and severely depressed inpatients).

Studying treatment-effect heterogeneity in precision medicine through induced subgroups.

Precision medicine, in the sense of tailoring the choice of medical treatment to patients' pretreatment characteristics, is nowadays gaining a lot of attention. Preferably, this tailoring should be realized in an evidence-based way, with key evidence in this regard pertaining to subgroups of patients that respond differentially to treatment (i.e., to subgroups involved in treatment-subgroup interactions). Often a-priori hypotheses on subgroups involved in treatment-subgroup interactions are lacking or are incomplete at best. Therefore, methods are needed that can induce such subgroups from empirical data on treatment effectiveness in a post hoc manner. Recently, quite a few such methods have been developed. So far, however, there is little empirical experience in their usage. This may be problematic for medical statisticians and statistically minded medical researchers, as many (nontrivial) choices have to be made during the data-analytic process. The main purpose of this paper is to discuss the major concepts and considerations when using these methods. This discussion will be based on a systematic, conceptual, and technical analysis of the type of research questions at play, and of the type of data that the methods can handle along with the available software, and a review of available empirical evidence. We will illustrate all this with the analysis of a dataset comparing several anti-depressant treatments.

Difficult-to-treat depression: A clinical and research roadmap for when remission is elusive.

OBJECTIVES: The report considers the pros and cons of the most commonly used conceptual model that forms the basis for most clinical practice guidelines for depression. This model promotes the attainment of sustained symptom remission as the treatment goal based on its well-established prognostic and functional importance. Sustained remission is very unlikely, however, after multiple treatment attempts. Our current model propels many clinicians to continue to change or add treatments despite little chance for remission or full functional restoration and despite the increasing risk of more adverse events from polypharmacy. An alternative 'difficult-to-treat depression' model is presented and considered. It accepts that the treatment aims for some depressed patients may shift to optimal symptom control rather than remission. When difficult-to-treat depression is suspected, the many treatable causes of persistent depression must be assessed and addressed (given the importance of remission when attainable) before difficult-to-treat depression can be ascribed. The clinical and research implications of the difficult-to-treat depression model are discussed. CONCLUSION: Suspected difficult-to-treat depression provides a practical basis for considering when to conduct a comprehensive evaluation. Once difficult-to-treat depression is confirmed, treatment may better focus on optimal disease management (symptom control and functional improvement).