Melancholic features and treatment outcome to selective serotonin reuptake inhibitors in major depressive disorder: A re-analysis of the STAR*D trial.

BACKGROUND: Melancholia has been positioned as a qualitatively different form of Major Depressive Disorder (MDD). Some studies have suggested that melancholic MDD patients may show lower remission when receiving treatment with Selective Serotonin Reuptake Inhibitors, but this has not yet been explored in large, representative samples of MDD. METHODS: We used data from the STAR*D, a multisite randomized controlled trial (n = 4041). We defined melancholia status through the BA Melancholia Empirical Index, constructed using items from the Inventory of Depressive Symptomatology (IDSC). The main outcome of interest was symptomatic remission defined as a Quick Inventory of Depressive Symptoms (Clinician version) (QIDS-C) below or equal to 5. Inverse probability weighting was used to control for confounding. RESULTS: 3827 patients were eligible for this study. Melancholic patients were more likely to be unemployed, never married, to self-report an African American race, and to have a higher depressive severity. The adjusted 4-month probability of remission was 26.9 % (22.0, 45.5) for melancholic and 53.8 % (53.2, 58.5), for nonmelancholic patients. Compared with nonmelancholic, the difference in 4-month probability of remission was -26.9 % (-37.0, -15.6). Results were consistent across sensitivity analyses. LIMITATIONS: Items from IDSC were used as a surrogate measure of the BA Melancholia Index, and extrapolation of the results to agents other than citalopram and to psychotic MDD patients requires caution. CONCLUSIONS: Melancholic MDD patients showed lower probabilities of remission at 4-months receiving treatment with citalopram. The results of this study show how validly subtyping episodes could contribute to the personalized treatment of depression.

Clinical Characteristics of Melancholic and Nonmelancholic Depressions.

ABSTRACT: This study aimed to compare clinical-demographic features of melancholic and nonmelancholic depressions. We included 141 depressed inpatients classified as melancholic and nonmelancholic by the Sydney Melancholia Prototype Index (SMPI) and Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria. Results were controlled for confounders, including severity measures. Melancholic patients by both diagnostic systems were more severely depressed and presented more psychotic symptoms, neurological soft signs, and psychomotor disturbances. Melancholic patients classified by the SMPI were also older at illness onset and had fewer suicide attempts. After controlling for confounders, although all differences remained significant for SMPI diagnosis, the DSM-5 diagnosis of melancholia was only associated with further impaired motor sequencing. The results obtained with the SMPI support the hypothesis that melancholia has clinical features qualitatively different from those of nonmelancholic depressions. Contrarily, the DSM-5 specifier seems to reflect the severity of depressive episodes rather than core clinical features of melancholia.

Correlates of neurological soft signs in bipolar disorder.

Recent research has focused on neurological soft signs (NSS) in bipolar disorder (BD), but there is still scarce evidence on their correlates with other relevant variables. The aim of this study was to explore the association between NSS and clinical demographic, neurocognitive, and functional variables. Eighty-eight euthymic BD patients were included in whom NSS were assessed using the Neurological Evaluation Scale. All subjects performed an extensive neurocognitive battery selected to assess premorbid IQ, attention, language, verbal memory, and executive functions. Psychosocial outcomes were assessed by means of the Functioning Assessment Short Test. Among the demographical variables, NSS tended to be negatively associated with years of education and increased with age. Likewise, NSS were higher in BD type I than in BD type II, but independent of age at illness onset and number of previous affective episodes. There was a negative correlation between NSS and premorbid IQ, as well as with performance in attention, language, and executive functions. Results tended to be unchanged when controlled for potential confounders. Although NSS were associated with poor psychosocial functioning in the bivariate analysis, when added to a multiple regression model including neurocognition, these neurological features did not significantly contribute to the variance of the functional outcome. Our findings contribute to a better characterization of NSS in BD; their potential clinical and theoretical implications are discussed in the manuscript.

Neurocognitive function of patients with melancholic and non-melancholic major depressive episodes: An exploratory study.

OBJECTIVE: The aim of this exploratory study was to compare the neurocognitive performance of patients undergoing melancholic and non-melancholic major depressive episodes. Considering potential limitations of the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) specifier, we employed an additional tool that has proven useful in identifying melancholia (the Sydney Melancholia Prototype Index). METHODS: One hundred forty-one depressed inpatients were classified as melancholic or non-melancholic according to the Sydney Melancholia Prototype Index and the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) criteria and compared on a neurocognitive battery selected to assess attention and processing speed, verbal memory, working memory and executive functions. Results were controlled for several potential confounders. RESULTS: Patients diagnosed as melancholic by the two diagnostic systems displayed lower scores in executive measures, semantic verbal fluency and phonological verbal fluency. On attention and processing speed, patients with melancholia underperformed those with non-melancholic depression only when diagnosed by the Sydney Melancholia Prototype Index. After controlling for confounders, associations between melancholic status and executive dysfunction remained significant for the Sydney Melancholia Prototype Index but not for the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) diagnosis. CONCLUSION: In this study, melancholia diagnosed by the Sydney Melancholia Prototype Index (but not by the Diagnostic and Statistical Manual of Mental Disorders [5th ed.] criteria) was characterized by a greater compromise of tests assessing executive functions than non-melancholic depressions, even after controlling for depressive severity. These preliminary results might contribute to generating hypotheses about differences in the cognitive profile and pathophysiological substrate between melancholic and non-melancholic depressions. Likewise, the pattern of findings supports the hypothesis that the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) melancholia specifier might identify more severe forms of depressive episodes rather than a qualitatively different subtype.

Revisiting the concept of bipolar depression: comparison of diagnostic validators between melancholic and non-melancholic episodes.

The current definition of bipolar disorder derives with minimal changes from one that emerged through expert consensus in the late 1970s, and the topic of its validity tended to be neglected in the literature. The aim of this exploratory study was to compare patients with bipolar disorder with a history of melancholic and non-melancholic depressive episodes in a series of external diagnostic validators. One hundred eight subjects were categorized as melancholic or non-melancholic in relation to their history of depressive episodes through the clinician-rated Sydney Melancholia Prototype Index (SMPI). The external validators used were clinical-demographic variables, family history of bipolar disorder, neurocognitive performance and functional outcome. There were 43.5% of the patients with a history of melancholia and 56.5% of non-melancholic depression. Non-melancholic depressions were overrepresented in females, while melancholic depressions had a female:male ratio closer to unity. Patients with melancholia had more history of BD in first-degree relatives and better functional outcome than those with non-melancholic depression. There were no differences between groups regarding neurocognitive performance. Results tended to be unchanged when controlled for confounders. Our preliminary results highlight the inherent heterogeneity in the current concept of bipolar depression, and suggest the need for further clinical research to elucidate its validity.

Clinical Course in Patients With Melancholic and Nonmelancholic Bipolar Depression.

ABSTRACT: The aim of the current study was to compare the longitudinal clinical course of patients with a history of melancholic and nonmelancholic bipolar depression. Seventy-seven euthymic outpatients with bipolar disorder were categorized as melancholic or nonmelancholic through the clinician-rated Sydney Melancholia Prototype Index. Clinical course was assessed for a period longer than 48 months by time spent ill, density of affective episodes, severity and duration of depressive episodes, and time to depressive recurrence. The mean follow-up time was 69.05 months. Patients with melancholic depressions had more severe and longer depressive episodes during follow-up, whereas patients with nonmelancholic depressions had a shorter time to depressive recurrence and more subsyndromal depressive symptoms and affective instability. These findings highlight the heterogeneity inherent to the current construct of bipolar depression and position melancholia as an interesting target for comparison with nonmelancholic depressions in other external validators in the field of bipolar disorder.

Bipolar Depression: A Historical Perspective of the Current Concept, with a Focus on Future Research.

ABSTRACT: The aim of this narrative review is to trace the origin of the concept of bipolar depression and to expose some of its limitations. Bipolar depression is a broad clinical construct including experiences ranging from traditional melancholic and psychotic episodes ascribed to "manic-depressive insanity," to another heterogeneous group of depressive episodes originally described in the context of binary models of unipolar depression (e.g., psychogenic depression, neurotic depression). None of the available empirical evidence suggests, however, that these subsets of "bipolar" depression are equivalent in terms of clinical course, disability, family aggregation, and response to treatment, among other relevant diagnostic validators. Therefore, the validity of the current concept of bipolar depression should be a matter of concern. Here, we discuss some of the potential limitations that this broad construct might entail in terms of pathophysiological, clinical, and therapeutic aspects. Finally, we propose a clinical research program for bipolar depression in order to delimit diagnostic entities based on empirical data, with subsequent validation by laboratory or neuroimaging biomarkers. This process will then aid in the development of more specific treatments.

Manic morbidity and executive function impairment as determinants of long-term psychosocial dysfunction in bipolar disorder.

OBJECTIVE: In this study, we aimed to evaluate the role of cognitive performance and measures of clinical course-including both syndromal and subsyndromal symptomatology-as determinants of the functional outcome of patients with Bipolar Disorder (BD) during a mean follow-up period of more than 4 years. METHODS: Seventy patients with euthymic BD completed a neurocognitive battery at study entry. Clinical course was assessed prospectively for a period longer than 48 months by two measures: time spent ill (documented using a modified life charting technique) and density of affective episodes (defined as the number of depressive and hypo/manic episodes per year of follow-up). Psychosocial functioning was assessed during euthymia using the Functioning Assessment Short Test (FAST) total score at the end of follow-up period. RESULTS: Baseline deficits in phonological fluency, a measure of executive functions (ß = -2.49; 95% CI = -3.98, -0.99), and density of hypo/manic episodes during follow-up (ß = 6.54; 95% CI = 0.43, 12.65) were independently associated with FAST total score at the end of study. CONCLUSIONS: Although interrelated, manic morbidity and executive function impairments independently contribute to long-term psychosocial dysfunction in BD and could be potential targets of intervention.

Personality Disturbances in Melancholic and Nonmelancholic Unipolar Major Depression: A Systematic Review and Meta-Analysis.

Although melancholic depression has been associated with a more adequate premorbid personality style, the empirical evidence supporting this statement is inconclusive. We conducted a systematic review and meta-analyzed studies comparing the presence of personality disturbances in melancholic and nonmelancholic subtypes of major depressive disorder (MDD). We defined a) a continuous outcome, defining personality traits as a dimensional construct, and b) a dichotomous outcome, defined as the presence/absence of personality disorders (PD). We also evaluated the role of potential moderators. Our results showed significantly higher levels of neuroticism and interpersonal sensitivity, and a higher likelihood of presenting a PD in nonmelancholic depression. No significant differences were found for extraversion. The scarcity of studies and high heterogeneity were among our limitations. In conclusion, personality disturbances seem to be overrepresented in nonmelancholic MDD. The assessment of personality disturbances can be useful in clinical practice and in the study of MDD heterogeneity.

Predictors of High Psychosocial Functioning in Bipolar Disorder.

The aim of this study was to identify predictors of high psychosocial functioning in patients with bipolar disorder (BD). One hundred forty-five outpatients with BD and 50 healthy controls were included. Patients were categorized as having high psychosocial functioning if they concomitantly met three conditions: a) General Assessment of Functioning greater than 90, b) full-time employment, and c) full functional recovery. Clinical, demographical, and neurocognitive variables were assessed and considered as potential predictors of high functioning in regression models. We found that 22.8% (n = 33) of patients exhibited high psychosocial functioning. BD type II, higher educational level, and better performance in verbal memory, attention, and executive functions were independent predictors of high psychosocial functioning. Our results provide evidence that functional outcomes are heterogeneous in BD, including a percentage of patients who maintain good to excellent psychosocial functioning despite their illness. Neurocognitive functioning could be one of the most influential factors to explain this heterogeneity.

Neurocognitive predictors of long-term clinical course in bipolar disorder.

OBJECTIVE: The aim of this study was to estimate whether neurocognitive deficits are predictors of the long-term clinical course of patients with bipolar disorder. METHODS: A total of 76 outpatients with bipolar disorder performed a neurocognitive assessment at baseline and were followed for a period of at least 48 months. The clinical course during the follow-up period was documented by two measures: (1) number of affective episodes and (2) time spent ill. RESULTS: Patients had lower performance than controls in the domains of verbal memory and executive functions, and they were followed-up for a mean period of 70.73 months. Global cognitive deficits (performance 1.5 standard deviations below the mean in two or more cognitive domain) were independent predictors of both hypo/manic episode density and time spent with hypo/manic symptoms during follow-up. On the contrary, no neurocognitive measure showed a relationship with depressive morbidity during follow-up. CONCLUSION: Our findings suggest that cognitive deficits could be useful for predicting hypo/manic morbidity in the long-term clinical course. Theoretical and clinical implications of these findings are discussed.

The structure of mania: An overview of factorial analysis studies.

BACKGROUND: Operational definitions of mania are based on expert consensus rather than empirical data. The aim of this study is to identify the key domains of mania, as well as the relevance of the different signs and symptoms of this clinical construct. METHODS: A review of latent factor models studies in manic patients was performed. Before extraction, a harmonization of signs and symptoms of mania and depression was performed in order to reduce the variability between individual studies. RESULTS: We identified 12 studies fulfilling the inclusion criteria and comprising 3039 subjects. Hyperactivity was the clinical item that most likely appeared in the first factor, usually covariating with other core features of mania, such as increased speech, thought disorder, and elevated mood. Depressive-anxious features and irritability-aggressive behavior constituted two other salient dimensions of mania. Altered sleep was frequently an isolated factor, while psychosis appeared related to grandiosity, lack of insight and poor judgment. CONCLUSIONS: Our results confirm the multidimensional nature of mania. Hyperactivity, increased speech, and thought disorder appear as core features of the clinical construct. The mood experience could be heterogeneous, depending on the co-occurrence of euphoric (elevated mood) and dysphoric (irritability and depressive mood) emotions of varying intensity. Results are also discussed regarding their relationship with other constitutive elements of bipolar disorder, such as mixed and depressive states.

Longitudinal analysis of cognitive performances in recent-onset and late-life Bipolar Disorder: A systematic review and meta-analysis.

OBJECTIVES: Neurocognitive deficits have been widely reported in euthymic Bipolar Disorder (BD) patients and contribute to functional disability. However, the longitudinal trajectory of these deficits remains a subject of debate. Although most research to this date shows that neurocognitive deficits tend to be stable among middle-age BD patients, it remains plausible that deterioration occurs at either early or late stages of this condition. METHODS: We conducted a comprehensive meta-analysis of studies that reported longitudinal neurocognitive performance among individuals with BD either within the year of their diagnosis or among late-life BD patients. Pooled effects of standardized mean differences (SMDs) for changes in neuropsychological scores over follow-up were estimated using random effects model. We also examined effect moderators, such as length of follow-up, mood state, or pharmacological load. RESULTS: Eight studies met inclusion criteria for recent-onset and four studies for late-life BD analysis. No evidence for a deterioration in neurocognitive functioning was observed among recent-onset BD patients (8 studies, 284 patients, SMD: 0.12, 95% CI -0.06 to 0.30, mean follow-up: 17 months) nor for late-life BD patients (4 studies, 153 patients, SMD: -0.35, 95% CI -0.84 to 0.15, mean follow-up: 33 months). None of the moderators were shown to be significant. CONCLUSIONS: These results, when appraised together with the findings in middle-life BD patients and individuals at genetic risk for BD, suggest that neurodevelopmental factors might play a significant role in cognitive deficits in BD and do not support the notion of progressive cognitive decline in most patients with BD.

Melancholia: An Attempt at Definition Based on a Review of Empirical Data.

We sought to identify clinical features that best discriminate melancholia from nonmelancholic depressive conditions. An extensive review of studies using latent factor models that identified a melancholic depression dimension/factor was undertaken. Clinical variables extracted from these studies were analyzed in terms of their contribution to a diagnosis of melancholia and their consistency across studies. Psychomotor retardation and mood nonreactivity were the most relevant clinical features for the identification of melancholic depressions. Other clinical features commonly described as weighted to melancholia, such as anhedonia, psychomotor agitation, late insomnia, or appetite/weight loss, seemed less useful in distinguishing these subtypes of depression. Study results are considered in relation to the potential limitations of current operational definitions of melancholia, and how symptom sets could be modified.

Social cognition in first episode bipolar disorder patients.

The aim of this study was to describe theory of mind (ToM) and emotional processing (EP) functioning in recently diagnosed bipolar disorder (BD). We evaluated 26 first episode BD (mean age 22.9 ±â€¯7.4) and 26 controls matched on age, gender, education, and premorbid intelligence. A significant poorer performance on the capacity of patients to infer other's intentions (cognitive ToM) that was partially independent from neurocognitive deficits (p < 0.01) as well as a lower recognition of fear was observed among patients. No significant association between any of these deficits and psychosocial functioning emerged in multivariate regression analyses.

Differential response to lithium between melancholic and non-melancholic unipolar depression.

The purpose of this report was to review the evidence regarding the differential response to lithium treatment between patients with unipolar melancholic and non-melancholic depression. Three studies suggest that the prophylactic effect of lithium in maintenance treatment may be greater in melancholic depression. Another study reported that melancholic symptoms, such as weight loss and psychomotor disturbances, predict a better response to lithium augmentation. These preliminary data suggest that the response to lithium may be greater in melancholic than in non-melancholic depression, which could be the focus of further research.