Characteristics of depressive and bipolar disorder patients with mixed features.

OBJECTIVE: To assess differences between subjects with vs. without mixed features in major affective disorders. METHODS: In 3099 out-patient subjects with DSM-5 major depressive disorder (MDD, n = 1921) or bipolar disorders (BD, n = 1178), we compared those with (Mx) vs. without (Non-Mx) mixed features (agitated-irritable depression or dysphoric [hypo]mania) in an index episode. RESULTS: Prevalence of Mx averaged 21.9% [CI: 20.5-23.4] overall, ranking: BD-II > BD-I > MDD, and in BD depression ≥ [hypo]mania > MDD. Mx subjects were significantly more likely than Non-Mx cases to (i) have other mixed episodes, (ii) have higher irritable and agitated ratings, (iii) have more substance abuse, (iv) switch into mixed episodes, (v) have more suicide attempts and higher suicidal ratings, (vi) change diagnosis from depression to BD, (vii) have higher hypomania scores when depressed or depression scores when [hypo]manic, (viii) be unmarried or separated with fewer children and siblings, (ix) be diagnosed more with BD than MDD, (x) be unemployed, (xi) have BD, suicide and divorce among first-degree relatives, (xii) be female, (xiii) be younger at illness-onset. Both BD and MDD Mx subjects also received antidepressants less, but antipsychotics and mood-stabilizers more, alone and in combination with antidepressants. CONCLUSIONS: Mood disorder subjects with agitated-irritable depression or dysphoric [hypo]mania differed from those without such mixed features, including having a less favorable clinical course and repeated mixed episodes. They may represent a distinct and prevalent, syndromal clinical subtype with prognostic and therapeutic significance.

Suicide attempts in bipolar disorders: comprehensive review of 101 reports.

OBJECTIVE: Assess reported risk of suicide attempts by patients with bipolar disorder (BD). METHOD: Systematic searching yielded 101 reports from 22 countries (79 937 subjects). We analyzed for risk (%) and incidence rates (%/year) of attempts, comparing sex and diagnostic types, including by meta-analysis. RESULTS: Attempt risk averaged 31.1% [CI: 27.9-34.3] of subjects, or 4.24 [3.78-4.70]%/year. In BD-I (43 studies) and BD-II subjects (30 studies), risks (29.9%, 31.4%) and incidence rates (4.01, 4.11%/year) were similar and not different by meta-analysis. Among women vs. men, risks (33.7% vs. 25.5%) and incidence (4.50 vs. 3.21%/year) were greater (also supported by meta-analysis: RR = 1.35 [CI: 1.25-1.45], P < 0.0001). Neither measure was related to reporting year, % women/study, or to onset or current age. Risks were greater with longer exposure, whereas incidence rates decreased with longer time at risk, possibly through 'dilution' by longer exposure. CONCLUSION: This systematic update of international experience underscores high risks of suicide attempts among patients with BD (BD-I = BD-II; women > men). Future studies should routinely include exposure times and incidence rates by diagnostic type and sex for those who attempt suicide or not.

Comparison of psychotic bipolar disorder, schizoaffective disorder, and schizophrenia: an international, multisite study.

OBJECTIVE: Nosological distinctions among schizoaffective disorder (SA), bipolar I disorder with psychotic features (BDp), and schizophrenia (SZ) remain unresolved. METHOD: We compared 2269 subjects with psychotic features in DSM-IV-TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating international sites, by 12 sociodemographic and clinical measures, all between diagnostic pairs. RESULTS: In bivariate comparisons, SA was consistently intermediate between BDp and SZ for 11/12 features (except onset stressors), and SZ vs. BDp differed in all 12 factors. SA differed from both BDp and SZ in 9/12 factors: SA and BDp were similar in education and suicidal ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse. Meta-analytic comparisons of diagnostic pairs for 10 categorical factors indicated similar differences of SA from both SZ and BDp. Multivariate modeling indicated significantly independent differences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs. SA (3). Measurement variance was similar for all diagnoses. CONCLUSION: SA was consistently intermediate between BDp and SZ. The three diagnostic groups ranked: BDp > SA > SZ related to lesser morbidity or disability. The findings are not consistent with a dyadic Kraepelinian categorization, although the considerable overlap among the three DSM-IV diagnostic groups indicates uncertain boundaries if they represent distinct disorders.

A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania.

BACKGROUND: Evidence synthesis methods enabling direct and indirect comparisons over the entire set of relevant clinical data produce quantitative point estimates for the treatments contrasts between competing interventions, and provide a hierarchical rank ordering between them. We aimed to provide evidence-based guidance on the efficacy and all-cause discontinuation of antimanic treatments. METHOD: We conducted a network meta-analysis within a Bayesian framework. We searched all standard literature databases without language restrictions up to 15 January 2014 to identify reports of short-term, randomized, blinded trials of putative antimanic drugs as monotherapy for adults with bipolar-I mania. RESULTS: Altogether, 14256 manic patients randomized to one of 18 active treatments or placebo provided 95 direct comparisons on 128 data points. For the primary outcome, standardized mean difference as Hedges' g (standardized mean difference; SMD), the hierarchies indicated by surface under the cumulative ranking (SUCRA) probabilities were in agreement with the point estimates for all antimanic drugs identified as effective. For the 12 effective antimanic drugs on clinical use, SMDs against placebo ranged from 0.32 to 0.66 without superiority of one over another, except for risperidone v. aripiprazole and valproate. Aripiprazole, olanzapine, quetiapine, risperidone, and valproate had less all-cause discontinuation rates than placebo. Sensitivity analysis by drug class indicated similar efficacy profiles for haloperidol, second-generation antipsychotics, and mood stabilizers. CONCLUSIONS: Hierarchical rank ordering by comparative efficacy and risk of all-cause discontinuations should help to guide antimanic treatment choices by clinicians, healthcare policy makers, and guideline developers.

First-episode types in bipolar disorder: predictive associations with later illness.

OBJECTIVE: Characteristics of initial illness in bipolar disorder (BD) may predict later morbidity. METHOD: We reviewed computerized clinical records and life charts of DSM-IV-TR BD-I or BD-II patients at affiliated mood-disorder centers to ascertain relationships of initial major illnesses to later morbidity and other clinical characteristics. RESULTS: Adult BD patient-subjects (N=1081; 59.8% BD-I; 58.1% women; 43% ever hospitalized) were followed 15.7±12.8 years after onsets ranking: depression (59%)>mania (13%)>psychosis (8.0%)≥anxiety (7.6%)≥hypomania (6.7%)>mixed states (5.5%). Onset types differed in clinical characteristics and strongly predicted later morbidity. By initial episode types, total time-ill ranked: mania≥hypomania≥mixed-states≥psychosis>depression>anxiety. Depression was most prevalent long-term, overall; its ratio to mania-like illness (D/M, by per cent-time-ill) ranked by onset type: anxiety (4.75)>depression (3.27)>mixed states (1.39)>others (all<1.00). The MDI (mania or hypomania-depression-euthymia interval) course-pattern was most common (34.4%) and associated with psychotic or manic onset; the depression before mania (DMI) pattern (25.0%) most often followed anxiety (38.8%), depression (30.8%), or mixed onsets (13.3%); both were predicted by initial mania depression sequences. CONCLUSION: First-lifetime illnesses and cycles predicted later morbidity patterns among BD patients, indicating value of early morbidity for prognosis and long-term planning.

Antecedents of manic versus other first psychotic episodes in 263 bipolar I disorder patients.

OBJECTIVE: As initial episode type can predict later morbidity in bipolar disorder, we tested the hypothesis that clinical antecedents might predict initial episode types. METHOD: We studied 263 first-episode, adult, DSM-IV-TR type I bipolar disorder (BD-I) subjects within the McLean-Harvard-International First-Episode Project. Based on blinded assessments of antecedents from SCID examinations and clinical records, we compared first lifetime manic vs. other (mixed, depressive, or non-affective) major psychotic episodes. RESULTS: We identified 32 antecedents arising at early, intermediate or later times, starting 12.3±10.7 years prior to first lifetime major psychotic episodes. Based on multivariate modeling, antecedents associated significantly and independently with other (n=113) more than manic (n=150) first lifetime major psychotic episodes ranked by odds ratio: more early attentional disturbances, more late depression, more early perplexity, more detoxification, more early unstable mixed affects, more antidepressants, more early dysphoria, more intermediate depression, more early impulsivity, more late anhedonia, longer early-to-intermediate intervals, more intermediate substance abuse, more family history of major depression, and younger at earliest antecedents. Antecedents selectively preceding manic more than other first psychotic episodes included more late behavioral problems and more risk of familial BD-I. CONCLUSION: Clinical antecedents in adult, BD-I patients, beginning a decade before first major episodes and progressing through sequential stages were dissimilar in manic vs. other first psychotic episodes.

Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics.

BACKGROUND: Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. METHODS: We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants, second-generation antipsychotics, or lithium for acute major depressive episodes in patients diagnosed with type I or II bipolar disorder and applied random-effects meta-analysis to evaluate their efficacy, comparing outcomes based on standardized mean drug-placebo differences (SMD) in improvement, relative response rates (RR), and number-needed-to-treat (NNT). RESULTS: We identified 24 trials of 10 treatments (lasting 7.5 weeks, with ≥ 50 collaborating sites/trial) that met eligibility criteria: lamotrigine (5 trials), quetiapine (5), valproate (4), 2 each for aripiprazole, olanzapine, ziprasidone, and 1 each for carbamazepine, lithium, lurasidone, and olanzapine-fluoxetine. Overall, pooled drug-over-placebo responder-rate superiority (RR) was moderate (29% [CI: 19-40%]), and NNT was 8.2 (CI: 6.4-11). By SMD, apparent efficacy ranked: olanzapine + fluoxetine ≥ valproate > quetiapine > lurasidone > olanzapine, aripiprazole, and carbamazepine; ziprasidone was ineffective, and lithium remains inadequately studied. Notably, drugs were superior to placebo in only 11/24 trials (5/5 with quetiapine, 2/4 with valproate), and only lamotrigine, quetiapine and valproate had > 2 trials. Treatment-associated mania-like reactions were uncommon (drugs: 3.7%; placebo: 4.7%). DISCUSSION: Controlled trials of non-antidepressant treatments for bipolar depression remain scarce, but findings with olanzapine-fluoxetine, lurasidone, quetiapine, and perhaps carbamazepine and valproate were encouraging; lithium requires adequate testing.

Heterogeneity of schizoaffective disorder compared with schizophrenia and bipolar disorder.

OBJECTIVE: Low diagnostic reliability, the need to meet criteria of two disorders, and its status as residual diagnosis in clinical practice led us to hypothesize that schizoaffective disorder (SAD) is characterized by considerable heterogeneity, particularly in comparison with schizophrenia (SZ) and bipolar disorder (BD). As this has not been investigated the aim of this study is to test whether heterogeneity is larger in SAD than in SZ and BD. METHOD: Systematic search for studies simultaneously comparing all three diagnoses regarding demographic, clinical, psychometric (clinical rating scales and IQ tests), and biological parameters; comparison of heterogeneity as measured by standard deviation (SD). RESULTS: Standard deviation of SAD samples (N = 47) was smaller than in both differential diagnoses. SDs were 7% higher in BD than in SAD (SZ: 2% higher); in studies employing DSM-IIIR/-IV pooled SD was 4% higher in BD (8% lower in SZ). Differences between diagnoses were limited to the comparison of SAD and BD, and became smaller when only psychotic BD was considered. CONCLUSION: Heterogeneity of SZ and BD is not smaller than that of SAD. SAD seems not to be more diverse than other functional psychoses. Results are preliminary because of the novelty of the approach and to the small number of studies.

Clinical responses to antidepressants among 1036 acutely depressed patients with bipolar or unipolar major affective disorders.

OBJECTIVE: Whether responses to antidepressants differ in bipolar and unipolar depression remains unresolved. METHOD: We analyzed patient characteristics and outcomes of antidepressant treatment of 1036 depressed patients with bipolar-I or bipolar-II disorder, or unipolar major depression, using bivariate and multivariate methods and survival analysis, testing the hypothesis that responses would be superior in unipolar depression. RESULTS: Antidepressants were given to 84.8% (878/1036) of depressed patients: 58.9% of 93 bipolar-I, 80.1% of 117 bipolar-II, and 91.3% of 668 unipolar disorder cases. The 158 not given antidepressants had more manias/year, spent more months in mania and depression, and were far more likely to receive mood stabilizers or antipsychotics long term. Improvement of HDRS21 depression ratings ranked: bipolar-II (69.6%) > bipolar-I (62.9%) > unipolar (57.9%; P < 0.0001), independent of initial illness severity. Responder rates (≥50% improved without switching) ranked: bipolar-II (77.0%) > bipolar-I (71.6%) > unipolar (61.7%; P < 0.0001). Remission rates (final HDRS < 7) ranked: 54.0%, 50.6%, and 40.8% respectively (P = 0.02); 67.5% remitted within 12 weeks of treatment. Survival-computed median time to remission (15.0 weeks, overall) was shortest for bipolar-II patients (10.7 weeks). The 3-month risk of switching into mania-hypomania ranked: bipolar-II (15.8%) > bipolar-I (8.60%) > unipolar (0.56%). Multivariate modeling found bipolar diagnosis, shorter latency to remission, more recent trial year, and fewer weeks depressed before treatment to be associated with greater percent improvement of HDRS ratings. CONCLUSION: Selective use of antidepressants with or without mood stabilizers in non-agitated, depressed bipolar disorder patients for short periods was effective with moderate risk of potentially dangerous, manic mood elevation.

Predominant recurrence polarity among 928 adult international bipolar I disorder patients.

OBJECTIVE: To test the hypothesis that patients with bipolar disorder (BPD) differ demographically and clinically within subgroups based on the predominant-polarity of major recurrences. METHOD: We tested factors for association with predominantly (≥2 : 1) depressive vs. mania-like episodes with 928 DSM-IV type-I BPD subjects from five international sites. RESULTS: Factors preliminarily associated with predominant-depression included: electroconvulsive treatment, longer latency-to-BPD diagnosis, first episode depressive or mixed, more suicide attempts, more Axis-II comorbidity, ever having mixed-states, ever married, and female sex. Predominant-mania was associated with: initial manic or psychotic episodes, more drug abuse, more education, and more family psychiatric history. Of the 47.3% of subjects without polarity-predominance, risks for all factors considered were intermediate. Expanding the definition of polarity-predominance to ≥51% added little, but shifting mixed-states to 'predominant-depression' increased risk of suicidal acts from 2.4- to 4.5-fold excess over predominant-mania-hypomania, and suicidal risk was associated continuously with increasing proportions of depressive or mixed episodes. CONCLUSION: Subtyping by predominant-polarity yielded predictive associations, including the polarity of first episodes and risk of suicide attempts. Such subtyping may contribute to improve planning of clinical care and to biological studies of BPD.

Reproduction among 1975 Sardinian women and men diagnosed with major mood disorders.

OBJECTIVE: Disability varies in patients with major affective disorders [type I and II bipolar disorders (BPD) and recurrent unipolar major depressive disorder (UP-MDD)]. It may include reproductive functioning, which has rarely been studied systematically. METHOD: We compared information acquired over several years pertaining to marital/reproductive status among 1975 systematically evaluated, treated, and followed women (n = 1351) and men (n = 624) diagnosed with DSM-IV type I (n = 300) or II BPD (n = 223), or MDD (n = 1452). We compared factors between patients with vs. without children and associated with fertility rate (children/fertile years × 100), using standard bivariate methods followed by multivariate modeling. RESULTS: Childless patients were younger at illness onset, more likely men, diagnosed with type I BPD, more educated, and unmarried, but similar in many aspects of clinical history to those with children. Fertility rate ranked: BP-I < BP-II ≤ MDD, and men < women. Mood-disorder patients had 17% fewer children/person than in the comparable general population of Sardinia. Among mood-disorder patients, fertility appeared to decline in Sardinia in recent decades, more in men than women. CONCLUSION: Type I BPD was associated with lower fertility than BP-II or UP-MDD, consistent with their relatively high levels of other disabilities.

Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: a meta-analytic review.

BACKGROUND: Since there is considerable uncertainty about therapeutic responses to antidepressants among depressed patients diagnosed with bipolar (BP) vs. unipolar (UP) mood disorders, we have reviewed available studies that compared both types of depressed patients. METHODS: Extensive computerized literature-searching identified reports of antidepressant studies involving both BP and UP depressed patients. We used random-effects meta-analysis to compare short-term drug responses by patient type, as well as meta-regression modeling for effects of selected covariates. RESULTS: We identified only 10 studies meeting even liberal inclusion criteria, and they varied greatly in size and design quality. The overall difference in antidepressant responses between BP (n=863) and UP (n=2 226) disorder patients was not significant (pooled RR=1.05; CI: 0.96-1.15; P=0.34). Based on meta-regression, we also found no difference in responses based on diagnosis or subtype, subjects/study, % women, average age, or length of treatment based on meta-regression. Risk of manic-switching averaged 2.50 vs. 0.275%/week among BP vs. UP disorder patients, including co-treatment with mood stabilizers in 70% of BP patients. COMMENTS: The findings suggest little difference in antidepressant responses by diagnostic type, sex, or other factors considered, but a substantial risk of mania and hypomania with BP disorders. However, data pertaining to the fundamental question of antidepressant response among BP vs. UP depressed patients were strikingly limited, and support only tentative conclusions. Additional, well-designed, prospective trials of matched BP and UP depression patients and controlled treatment are required.

Mania associated with antidepressant treatment: comprehensive meta-analytic review.

OBJECTIVE: To review available data pertaining to risk of mania-hypomania among bipolar (BPD) and major depressive disorder (MDD) patients with vs. without exposure to antidepressant drugs (ADs) and consider effects of mood stabilizers. METHOD: Computerized searching yielded 73 reports (109 trials, 114 521 adult patients); 35 were suitable for random effects meta-analysis, and multivariate-regression modeling included all available trials to test for effects of trial design, AD type, and mood-stabilizer use. RESULTS: The overall risk of mania with/without ADs averaged 12.5%/7.5%. The AD-associated mania was more frequent in BPD than MDD patients, but increased more in MDD cases. Tricyclic antidepressants were riskier than serotonin-reuptake inhibitors (SRIs); data for other types of ADs were inconclusive. Mood stabilizers had minor effects probably confounded by their preferential use in mania-prone patients. CONCLUSION: Use of ADs in adults with BPD or MDD was highly prevalent and moderately increased the risk of mania overall, with little protection by mood stabilizers.

Age at onset in 3014 Sardinian bipolar and major depressive disorder patients.

OBJECTIVE: To test if onset age in major affective illnesses is younger in bipolar disorder (BPD) than unipolar-major depressive disorder (UP-MDD), and is a useful measure. METHOD: We evaluated onset-age for DSM-IV-TR major illnesses in 3014 adults (18.5% BP-I, 12.5% BP-II, 69.0% UP-MDD; 64% women) at a mood-disorders center. RESULTS: Median and interquartile range (IQR) onset-age ranked: BP-I = 24 (19-32) < BP-II = 29 (20-40) < UP-MDD = 32 (23-47) years (P < 0.0001), and has remained stable since the 1970s. In BP-I patients, onset was latest for hypomania, and depression presented earlier than in BP-II or UP-MDD cases. Factors associated with younger onset included: i) being unmarried, ii) more education, iii) BPD-diagnosis, iv) family-history, v) being employed, vi) ever-suicidal, vii) substance-abuse and viii) ever-hospitalized. Onset-age distinguished BP-I from UP-MDD depressive onsets with weak sensitivity and specificity. CONCLUSION: Onset age was younger among BPD than MDD patients, and very early onset may distinguish BPD vs. UP-MDD with depressive-onset.

Prospective, open study of long-acting injected risperidone versus oral antipsychotics in 88 chronically psychotic patients.

INTRODUCTION: A long-acting, injected, carbohydrate-microsphere preparation of risperidone (RLAI; Risperdal Consta ((R))) is reported to be safe and effective in chronic psychotic illnesses but, as its long-term and comparative efficacy remain unclear, this study compared clinical status during oral antipsychotic treatment versus conversion to RLAI. METHODS: Psychotic patients (n=88; initial BPRS=93+/-5) were treated for 6 months with clinically chosen oral medication and then converted to biweekly RLAI for the first 6 months (6-6 months matched mirror comparison) and then for another 18 months. Clinical status in the two treatment periods and in the 18 months of follow-up was compared with measures including BPRS improvement (primary outcome), CGI variants and SF-36 ratings. RESULTS: RLAI (at a mean dose of 47 mg/2 weeks at six and up to 23.1+/-3.3 months) was associated with major improvements in all outcome measures (p<0.001). Initial BPRS scores fell by an average of 50% within six months; hospitalizations declined from 19.8% to 0%, and rates of adverse events were reduced by 2.5- to 7.4-fold. Such benefits were sustained during 18 months of follow-up with RLAI-treatment. CONCLUSIONS: The findings are limited by the lack of a parallel control treatment, such as with oral risperidone or another antipsychotic, lack of blinded assessments, and a moderate number of subjects. Nevertheless, the findings add to indications that RLAI can be an effective and well-tolerated treatment-option for chronically psychotic patients.

Characteristics and clinical changes during hospitalization in bipolar and psychotic disorder patients with versus without substance-use disorders.

BACKGROUND: Co-morbid substance-use disorders (SUDs) are prevalent among patients with severe psychiatric disorders, but the characteristics of such patients remain incompletely defined, and their current treatments and responses, poorly documented. METHODS: We evaluated the records of 481 consecutive inpatients diagnosed with DSM-IV bipolar or schizoaffective disorders, or schizophrenia, admitted to McLean Hospital in 2004 or 2009. Demographic and clinical characteristics, and treatments, were extracted from hospital and pharmacy records for bivariate and multivariate analyses. RESULTS: SUD prevalence increased 1.84-times from 2004 (31.3%) to 2009 (57.6%). Patients with (n=204) versus without co-morbid SUDs (n=277) were similar in many respects, but in multivariate modeling, the following factors were more likely with SUD, in rank-order: co-morbid anxiety disorders > men more than women > greater prevalence in 2009 vs. 2004 > younger age > greater doses of mood-stabilizers > shorter hospitalization. CONCLUSIONS: Hospitalized patients with severe primary psychiatric disorders, and comorbid SUD were more likely to be young and have anxiety disorders, to receive more combinations and higher doses of mood-stabilizers, and show more improvement in impulsivity and hostility, but otherwise differed little in treatment-responses. Prevalence of SUD rose substantially in the past five years, with increased but largely unproved use of mood-stabilizers.

Suicidal Risks in 12 DSM-5 Psychiatric Disorders.

OBJECTIVE: As modern studies evaluating suicidal behaviors in large samples of major psychiatric disorder patients are rare, we compared suicidal risks associated with a variety of psychiatric diagnoses. METHODS: We quantified rates of intake suicidal ideation and lifetime attempts, suicides, and violent acts (attempts + suicides) in 6050 adult patients in a European psychiatric center, diagnosed with 12 prevalent, DSM-5 psychiatric disorders. RESULTS: Ideation ranged from 53.9% of subjects with bipolar disorder (BD) with mixed features, to 8.70% in anxiety disorders. Subjects making at least one suicide attempt were most prevalent in BD with mixed or psychotic features. Suicide rates ranked: substance abuse > BD with psychotic features > psychotic disorders ≥ BD-I > major depressive disorder (MDD). Suicidal intensity (acts/100 PEY) was highest with BD, psychotic disorders, and MDD; lethality (lower attempt/suicide ratio) was greatest with substance abuse, psychotic disorders, and BD with psychotic features. Rates of suicidal acts in BD vs. MDD were similarly high among ever-hospitalized subjects but much lower in never-hospitalized MDD subjects. Women had higher overall risks of ideation and attempts, but violent acts and suicide were more likely among men, whereas SMR for suicide was greater among women, presumably reflecting very low risks among women in the regional general population. CONCLUSIONS: Suicidal risks were particularly high in BD with psychotic or mixed features as well as with substance abuse and in severe MDD with hospitalization.

Melancholic versus Nonmelancholic Major Depression Compared.

BACKGROUND: The concept of melancholia has been associated with psychiatric nosology for centuries. Nevertheless, its definition, relationship to the contemporary concept of Major Depressive Disorder, and clinical implications remain uncertain. METHODS: In a total sample of 3211 closely evaluated patient-subjects diagnosed with DSM-5 Major Depressive or Bipolar Disorder and meeting DSM-5 criteria for major depression with melancholic features or not at a European mood disorder center, we matched 1833 for depression severity (baseline HDRS21 score ≥18) and compared rates and ratings of characteristics of interest between the subgroups, using bivariate and multivariate methods. RESULTS: Observed prevalence of melancholic features was 35.2% in the 1833 subjects matched for severity, and 21.0% among all 3211 subjects. Diagnosis was highly dependent on depression-severity measured three ways. Very few clinical characteristics differed between melancholic and nonmelancholic subjects matched for illness-severity; more suicidal ideation with melancholic features was a notable exception. CONCLUSIONS: Study findings leave the distinction of melancholic features from depression-severity unclear and the potential clinical value of diagnosing melancholic features uncertain.