AimsTo identify early clinical factors predictive of later morbidity in major depressive disorder (MDD).MethodsWe analysed factors associated with long‐term depressive morbidity (%‐time ill) between a first‐lifetime major depressive episode and last follow‐up of 116 adults diagnosed with DSM‐IV major depressive disorder. Bivariate comparisons were followed by multivariable linear regression modelling.ResultsThree factors were independently associated with an average of 25%‐time‐depressed over 17 years at risk: (a) agitated‐mixed, or psychotic features in initial major depressive episodes, (b) anxiety syndromes prior to a first‐lifetime major depressive episode, and (c) anxiety symptoms in childhood.ConclusionEarly anxiety symptoms and syndromes and agitated‐mixed or psychotic initial depressive episodes predicted more long‐term depressive morbidity in MDD.

The objective of this study was to identify the predictive value of juvenile factors for adult suicidal behavior. We reviewed clinical records to compare factors identified in childhood and adolescence between adult suicidal versus nonsuicidal major affective disorder subjects. Suicide attempts occurred in 23.1% of subjects. Age-at-first-symptom was 14.2 vs. 20.2 years among suicidal versus nonsuicidal subjects (p < 0.0001). More prevalent in suicidal versus non-suicidal subjects by multivariate analysis were: depressive symptoms, hyper-emotionality, younger-at-first-affective-episode, family suicide history, childhood mood-swings, and adolescence low self-esteem. Presence of one factor yielded a Bayesian sensitivity of 64%, specificity of 50%, and negative predictive power of 86%. Several juvenile factors were associated with adult suicidal behavior; their absence was strongly associated with a lack of adult suicidal behavior.

BACKGROUNDDeveloping safe and effective long-term treatments for bipolar disorder remains a major challenge. Given available treatments, patients with bipolar disorder remain unwell in half of long-term follow-up, mostly in depression. As memantine, an N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist used to treat dementia, has been proposed for testing in bipolar disorder, we carried out a 3 + 3-year, mirror-image, chart-review study of the effects of adding memantine to stably continued, but insufficiently effective, ongoing mood-stabilizing treatments.METHODOutpatients diagnosed with DSM-IV-TR bipolar disorder (I or II), followed intensively at the Lucio Bini Mood Disorder Center, Rome, Italy, had responded consistently unsatisfactorily to standard treatments (lithium, anticonvulsants, antipsychotics, antidepressants, and electroconvulsive therapy) for ≥ 3 years (2005-2013). Memantine (20-30 mg/d) was added clinically to otherwise stable regimens for another 3 years. On the basis of chart review, we compared morbidity measures and Clinical Global Impressions scale for Bipolar Disorder (CGI-BP) score before versus during memantine treatment.RESULTSThe 30 bipolar I (n = 17) and II (n = 13) subjects showed consistent morbidity for 3 years before memantine, but improved progressively (r = 0.28, P < .01) over 3 years with memantine (23 ± 4.8 mg/d). Markedly decreased (all P values ≤ .01) were (1) percentage of time ill (total, mania, or depression; averaging -75.0%), (2) CGI-BP severity scores (-67.8%), (3) duration of new episodes (-58.6%), and (4) episodes/year (-55.7%). Subjects with previous rapid or continuous cycling were particularly improved (t = 2.61, P = .016). Adverse effects were mild and rare.CONCLUSIONSMemantine added substantial long-term benefits by preventing or ameliorating depressive as well as mania-like morbidity in previously consistently poorly responsive patients with bipolar disorder. Further testing in randomized, controlled trials is required.

OBJECTIVE To evaluate the presence of affective signs and symptoms as precursors of bipolar disorder in prospective studies, including assessment of their prevalence, duration, and predictive value. DATA SOURCES We followed PRISMA guidelines to search PubMed, CINAHL, PsycINFO, EMBASE, SCOPUS, and ISI Web of Science databases to May 31, 2013, using the terms bipolar disorder AND (antecedent* OR predict* OR prodrom* OR prospect*) AND (diagnosis OR development). Hand searching of identified reports led to additional relevant references. STUDY SELECTION We included only English-language articles containing (1) prospective, longitudinal studies with at least 2 structured clinical assessments (intake and follow-up); (2) no previous DSM-III or DSM-IV diagnoses of bipolar I or bipolar II; and (3) diagnostic outcome of bipolar I or bipolar II. Studies of subjects at familial risk of bipolar disorder were excluded, as these have been reviewed elsewhere. DATA EXTRACTION We tabulated details of study design, outcomes, precursors, and predictive value. Only studies reporting a positive predictive association were included. RESULTS In 26 published reports meeting selection criteria, methods varied widely in terms of design, duration of follow-up, ages, and populations investigated. Despite such heterogeneity in methods, findings were notably consistent. Precursors of bipolar disorder include mood lability, subsyndromal and major depression, subsyndromal hypomanic symptoms with or without major depression, cyclothymia and bipolar not otherwise specified, major depression with psychotic features, and other psychotic disorders. Bipolar disorder was also predicted by juvenile onset of major depression as well as frequency and loading of hypomanic or depressive symptoms. CONCLUSIONS Despite the limitations of published reports, prospectively identified precursors of bipolar disorder typically arose years prior to syndromal onset, often with significant early morbidity and disability. Prospectively identified precursors of bipolar disorder are generally consistent with findings in retrospective and family-risk studies. Combining precursors and other risk factors may increase predictive value, support earlier diagnosis, improve treatment, and limit disability in bipolar disorder.

We have recently reported that memantine has a clinically relevant antimanic and long-lasting mood-stabilizing effect in treatment-resistant bipolar disorders, both as augmenting agent and as monotherapy. We have also observed an acute antimanic and sustained mood-stabilizing effect in a small number of patients with bipolar I disorder who had had minimal previous pharmacotherapy. In this article, we report the case of a young woman suffering from bipolar II disorder with associated fibromyalgia, in whom memantine showed an acute antimanic and a long-term prophylactic effect on both bipolar disorder as well as the associated fibromyalgia syndrome.

Background: Mixed depression (MxD) is narrowly defined in the DSM-IV and somewhat broader in the DSM-5, although both exclude psychomotor agitation as a diagnostic criterion. This article proposes a clinical description for defining MxD, which emphasizes psychomotor excitation. Methods: Two hundred and nineteen consecutive outpatients were diagnosed with an MxD episode using criteria proposed by Koukopoulos et al. [Acta Psychiatr Scand 2007;115(suppl 433):50-57]; we here report their clinical features and antidepressant-related effects. Results: The most frequent MxD symptoms were: psychic agitation or inner tension (97%), absence of retardation (82%), dramatic description of suffering or weeping spells (53%), talkativeness (49%), and racing or crowded thoughts (48%). MxD was associated with antidepressants in 50.7% of patients, with similar frequency for tricyclic antidepressants (45%) versus selective serotonin reuptake inhibitors (38.5%). Positive predictors of antidepressant-associated MxD were bipolar disorder type II diagnosis, higher index depression severity, and higher age at index episode. Antipsychotic or no treatment was protective against antidepressant-associated MxD. Conclusions: MxD, defined as depression with excitatory symptoms, can be clinically identified, is common, occurs in both unipolar depression and bipolar disorder, and is frequently associated with antidepressant use. If replicated, this view of MxD could be considered a valid alternative to the DSM-5 criteria for depression with mixed features.

Background: Better and earlier predictive differentiation of bipolar (BD) vs unipolar major depressive disorder (UD) diagnoses should improve long-term clinical planning.Methods: We reviewed randomly selected clinical records of 334 adults diagnosed with DSM-IV-TR BD-1 (n=109), BD-ll (n=106), and UD (n=119) and compared features preceding major affective episodes or diagnoses, using bivariate, multivariate, and Bayesian methods.Results: We identified antecedents selectively associated with later BD vs. UD in 52.6% vs. 31.1% of subjects in childhood, starting at age 74 years, and 60.0% vs. 32.8% in adolescence, with far more features in BD than LID cases (10.3 vs. 4.64/100 person years; p < 0.001). In multivariate modeling, BD selective factors were: younger at first clinical event > male sex > family BD history > cyclothymic or hyperthymic temperament > antecedents/person-year. Nonaffective (anxiety, eating, or substance use) disorders preceded BD vs. UD in 41.4% vs. 28.6% of subjects (p=0.02). By ROC analysis, differential prediction of BD vs. UD was optimal with any >3 factors/person. Limitations: The validity and timing of antecedent events and factors identified retrospectively from clinical records could not be verified independently, but information was recorded systematically and consistently by a single mood disorder expert prior to diagnosis, and extracted by two independent observers.Comment: Early clinical features distinguished later BD from UD, often by years. Such prediction should improve treatment planning and limit risk of mood switching, (C) 2014 Elsevier By. All rights reserved

Background: Mixed depression (MxD) is one subtype of depressive experiences within the depressive spectrum. MxD definition is debated among experts. Koukopoulos proposed diagnostic criteria focused primarily on psychic agitation, marked irritability, and intense mood lability as markers of a mixed depressive episode. The present study vandal:es Koukopoulos' criteria as diagnostic for MxD.Methods: A sample of 435 patients from the International Mood Network (IMN), multi center. infernational network of sites, and the Centro LucioBini of Rome was analyzed. Koukopoulos' criteria were assessed in all patients.Results: The most prevalent MxD criteria were "absence of psychomotor retardation" (84%), "mood lability or marked reactivity" (78%), and "psychic agitation or inner tension" (75%). Multivariable predictors of a MxD (+) diagnosis were: higher current CGI (OR=1.23, 95% CI 123, 2.84), lower rates of previous bipolar type I diagnosis (OR=0.54, 95% Cl 3.28, -0.13), mixed symptoms on the index episode (OR=10.02, 95% Cl 2.32, 24.12), rapid cycling course (OR=2.6 95% Cl 1.45, 3.56), past substance abuse (OR=3.02, 95% Cl 2.01, 5.67) and lower education status (OR=0.44, 95% Cl - 3.23, 0.98). This model showed a sensitivity of 76.4%, specificity of 86.3%, negative predictive value of 75%, and positive predictive value of 86%.Limitations: An external validation of these criteria in an independent sample is warranted.Conclusion: A broad definition of mixed depression was internally validated with multiple diagnostic vandators and was sensitively and specifically predicted. Contrary to DSM-5, Koukopoulos' broad criteria include agitation, irritability and mood lability as core features. (C) 2014 Elsevier B.V. All rights reserved

Discontinuation of long-term lithium treatment leads to early and severe affective recurrences [Baldessarini et al. 1999], and to a bipolar disorder course more severe than that before lithium treatment with an increased risk of suicide [Post, 2012], which is often resistant not only to other mood stabilizers, but also to the reinstitution of lithium treatment at the prior effective serum lithium level [Post, 2012]. Unfortunately, the currently available lithium-alternative mood stabilizers are of limited (anticonvulsants) [Geddes et al. 2010; Kessing et al. 2011; Greil and Kleindiest, 1999], or questionable (atypical neuroleptics) [Goodwin et al. 2011] efficacy. We have recently provided clinical observations strongly suggesting that memantine, a noncompetitive N-methyl D-aspartate receptor antagonist, has a clinically relevant antimanic and a sustained mood-stabilizing effect in treatment-resistant bipolar disorder with excellent safety and tolerability [Koukopoulos et al. 2010, 2012; Sani et al. 2012; Serra et al. 2013]. More recently we have observed a long-lasting mood-stabilizing effect of memantine after lithium discontinuation in a bipolar I patient [Serra et al. 2013]. In order to evaluate further the effect of memantine in the prophylaxis of affective recurrences occurring after long-term lithium discontinuation, we administered the drug to three patients who had to discontinue lithium because of severe renal complications (two patients) or excessive tremor (one patient). These case histories confirm our previous observations, and suggest that memantine may be considered a useful lithium substitute to prevent the affective recurrences after lithium discontinuation. Case 1 Woman born in 1930, suffering from a bipolar II disorder with rapid cycling course. She has a family history of bipolar disorder. Her first affective episode was a depression in May 1979 (aged 49 years), followed by a hypomania until January 1980. She started lithium prophylaxis and had a very good response to lithium. In June 2009 lithium was gradually reduced to 150 mg every 2 days (serum lithium level 0.2 mmol/L) and then withdrawn because of renal impairment. After we had obtained the informed written consent, she was put on 20 mg/day memantine and lamotrigine (250 mg/day). She started with rapid cycling recurrences until May 2010. Since then she has been well and stable on memantine 20 mg/day, lamotrigine 250 mg/day and lithium 150 mg every 2 days (lithium serum level 0.2 mmol/L).

We have recently reported that memantine has a clinically relevant antimanic and long-lasting mood-stabilizing effect in treatment- resistant bipolar disorders, both as augmenting agent and as a monotherapy. Moreover, we observed an acute antimanic and sustained mood-stabilizing effect also in "naïve" bipolar type I disorder. Here we report a case history of a young woman suffering from bipolar type II mood disorder, associated with a very severe eating disorder, showing an acute antimanic and a long-term prophylactic effect of memantine on bipolar disorder and comorbid eating disorder.

Serra, Giulia MD; De Chiara, Lavinia MD; Koukopoulos, Athanasios MD; Serra, Gino MD Author Information

The DSM system has never acknowledged a central position for mixed states; thus, mixed depressions have been almost completely neglected for decades. Now, DSM-5 is proposing diagnostic criteria for depression with mixed features that will lead to more misdiagnosis and inadequate treatment of this syndrome. Different criteria, based on empirically stronger evidence than exists for the DSM-5 criteria, should be adopted.

Objective: The nature of mixed mood episodes is still a matter of controversy amongst experts. Currently, the approach to this syndrome is mainly categorical and very restrictive. The factor-structure of bipolar mood episodes has not been studied yet. We performed a dimensional analysis of the structure of bipolar episodes aimed at identifying a factor deconstructing mixed episodes; furthermore, we analyzed correlations of factors emerging from the factorial analysis of the Brief Psychiatric Rating Scale (BPRS) with Temperament Evaluation of Memphis-Pisa-Paris-San Diego (TEMPS-A) and predominant polarity.Method: 187 consecutive bipolar I inpatients hospitalized for DSM-IV-TR acute mood episodes (depressive, manic or mixed) underwent a standardized assessment, including the 24-item Brief Psychiatric Rating Scale (BPRS 4.0), the 21-item Hamilton Depression Rating Scale (HDRS-21), the Young Mania Rating Scale (YMRS) and the TEMPS-A. Principal factor analysis was performed on BPRS-24 items.Results: This analysis revealed five factors corresponding to "psychosis", "euphoric mania", "mixity", "dysphoria" and "inhibited depression", capturing 71.89% of the rotated variance. The mixity factor was characterized by higher rates of suicidal ideation, more mixed episodes, higher frequencies of antidepressant (AD) use, depressive predominant polarity and anxious temperament.Discussion: The factor-structure of the BPRS in inpatients with bipolar I disorder with an acute episode of any type is pentafactorial; one factor identified is the mixity factor, which is independent from other factors and characterized by anxiety and motor hyperactivity and by the absence of motor retardation. Our results should prompt reconsideration of proposals for DSM-5 diagnostic criteria for the mixed features specifier. Limitations of the study include the relative small sample, the absence of drug-naive patients and the use of rating scales no specific for mixed states. (C) 2013 Elsevier B.V. All rights reserved.

Background: We have recently provided preliminary clinical observations indicating that memantine, as augmenting agent, was associated with a meaningful antimanic and mood-stabilizing effect in treatment-resistant bipolar disorders. To further investigate the therapeutic and prophylactic action of the drug we administered memantine, as augmenting agent, to 40 treatment-resistant bipolar disorder patients, monitored and evaluated for 12 months.Methods: The sample population encompassed 40 treatment-resistant bipolar disorder patients monitored for 12 months. Memantine, at the dose of 10-30 mg/day, was added to the ongoing treatment, which was left unmodified. The severity of the patients' condition before memantine and the changes after memantine addition were evaluated on the Clinical Global Impression Bipolar (CGI-BP) Overall Bipolar Illness Scale. The severity of patients' condition was scored before memantine and the change was evaluated after memantine addition at 6 and 12 months.Limitations: The present study has the limitations of an open clinical study and the observed effects require testing in a blinded, randomized, controlled trial which is planned.Results: The average CGI-BP score of the patients was 6.7 (SD = 0.58, range: 5-7) before the addition of memantine. After 6 months of memantine treatment, 72.5% of patients were very much or much improved. Among the rapid eyelets 68.4% of patients reached stability, defined by the absence of recurrences. Patients very much or much improved were 72.5% at 12 months; while 12.5% discontinued memantine or were lost to follow-up.Conclusions: The results confirm our previous observations and strongly suggest that memantine, as augmenting agent, was associated with a clinically substantial antimanic and sustained mood-stabilizing effect, with excellent safety and tolerability profile. (C) 2011 Elsevier B.V. All rights reserved.

Aims:The aim of this study was to identify predictors of completed suicide in a wide sample of psychiatric inpatients receiving retrospective and prospective DSM-IV diagnoses.Methods:We followed up 4441 severe psychiatric patients who were hospitalized for some time during a 35-year period in a private hospital setting. We collected sociodemographic, clinical and temperamental data.Results:Ninety-six patients from the sample committed suicide. There were no sex differences in suicide completion and no differences between major psychiatric disorders, but people who had been hospitalized for anxiety disorders did not commit suicide and people with bipolar disorders were more likely to commit suicide than people with unipolar major depression. Shorter-term treatment with lithium and anticonvulsants, longer-term treatment with antidepressants, history of suicide attempts, suicidal thinking, and single status positively predicted completed suicide. Suicide tended to occur after a mean period of about 14 years of duration of disease. Patients' symptoms during the period preceding suicide were assessed through interviewing patients' physicians or family members. Symptoms occurring in > 10% of cases were, in decreasing order, inner tension, racing/crowded thoughts, aggressive behavior, guilt, psychomotor agitation, persecutory ideation, anxiety, and hallucinations. Surprisingly, cyclothymic temperament was less associated with completed suicide as compared to other temperaments.Conclusions:Suicide is likely to occur in a milieu of agitation, mixed anxiety and depression, and psychosis. Longer-term mood stabilizer treatment may reduce the rate of completed suicide.

Back to table of contents Previous article Next article Communications and UpdatesFull AccessMelancholia as a Distinct Mood Disorder? Recommendations for DSM-5James H. Kocsis, M.D.James H. KocsisNew York, N.Y.Search for more papers by this author, M.D.Published Online:1 Dec 2010https://doi.org/10.1176/appi.ajp.2010.10070983AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: In an editorial in the July 2010 issue of the Journal, Gordon Parker, M.D. (1), and a distinguished group of 16 coauthors, including one of the Deputy Editors of this journal, made an argument for melancholia being classified as a distinct mood disorder. The arguments that 1) melancholia features a cluster of symptoms with greater consistency than the broad heterogeneity of the disorders and conditions included in major depression and bipolar disorder and 2) the melancholia diagnosis has superior predictability for prognosis and treatment were not well supported by the evidence. For example, the statement that melancholic patients rarely respond to placebos, psychotherapies, or social interventions could equally well apply to severe major depression and psychotic major depression, both of which are major depression subtypes, as is melancholia, allowed as “specifiers” in the DSM-IV classification of major depression. Relevant literature reveals that hypercortisolemia is not specific to the melancholia diagnosis (2, 3). More importantly, in many studies the melancholia diagnosis lacks predictive value for treatment selection, including response to antidepressant medications or differential predictive value for response across classes of antidepressants (4, 5). Because each of the specifiers designated in DSM-IV shares characteristics with the larger domain of major depression and yet each has its own distinctive qualities (for melancholia it is a characteristic cluster of symptoms), it makes sense to retain the current system in DSM-5.New York, N.Y.Dr. Kocsis has received research grant support from the Agency for Healthcare Research and Quality, the National Institute of Mental Health, the National Institute on Drug Abuse, AstraZeneca, Burroughs Wellcome Trust, CNS Response, Forest, Pritzker Consortium, and Roche; he has served on the speaker's bureaus of AstraZeneca, Merck, Pfizer, and Wyeth; and he has served on the advisory boards of Neurosearch, Pfizer, and Wyeth.This letter was accepted for publication in September 2010.References1. Parker G , Fink M , Shorter E , Taylor MA , Akiskal H , Berrios G , Bolwig T , Brown WA , Carroll B , Healy D , Klein DF , Koukopoulos A , Michels R , Paris J , Rubin RT , Spitzer R , Swartz C : Issues for DSM-5: Whither melancholia? The case for its classification as a mood disorder. Am J Psychiatry 2010; 167: 745–747Link, Google Scholar2. Stokes PE , Stoll PM , Koslow SH , Maas JW , Davis JM , Swann AC , Robins E : Pretreatment DST and hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups: a multicenter study. Arch Gen Psychiatry 1984; 41: 257–267Crossref, Medline, Google Scholar3. American Psychiatric Association Task Force on Laboratory Tests in Psychiatry : The Dexamethasone Suppression Test: an overview of its current status in psychiatry. Am J Psychiatry 1987; 144: 1253–1262Link, Google Scholar4. Hirschfeld RM : Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs. J Clin Psychiatry 1999; 60: 326–335Crossref, Medline, Google Scholar5. Mallinckrodt CH , Watkin JG , Liu C , Wohlreich MM , Raskin J : Duloxetine in the treatment of major depressive disorder: a comparison of efficacy in patients with and without melancholic features. BMC Psychiatry 2005; 5: 1Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByFrom dysthymia to treatment-resistant depression: evolution of a psychopathological construct21 May 2020 | International Review of Psychiatry, Vol. 32, No. 5-6Persistent Depressive Disorder: Commentary on Parker and Malhi26 June 2019 | The Canadian Journal of Psychiatry, Vol. 65, No. 1Should psychomotor disturbance be an essential criterion for a DSM-5 diagnosis of melancholia?31 May 2013 | BMC Psychiatry, Vol. 13, No. 1DSM-5: a collection of psychiatrist views on the changes, controversies, and future directions12 September 2013 | BMC Medicine, Vol. 11, No. 1Current Opinion in Psychiatry, Vol. 25, No. 1 Volume 167Issue 12 December 2010Pages 1534-1534 Metrics PDF download History Accepted 1 September 2010 Published online 1 December 2010 Published in print 1 December 2010

Back to table of contents Previous article Next article EditorialFull AccessIssues for DSM-5: Whither Melancholia? The Case for Its Classification as a Distinct Mood DisorderGordon Parker, M.D., Max Fink, M.D., Edward Shorter, Ph.D., Michael Alan Taylor, M.D., Hagop Akiskal, M.D., German Berrios, M.D., Tom Bolwig, M.D., Walter A. Brown, M.D., Bernard Carroll, M.B.B.S., David Healy, M.D., Donald F. Klein, M.D., Athanasios Koukopoulos, M.D., Robert Michels, M.D., Joel Paris, M.D., Robert T. Rubin, M.D., Robert Spitzer, M.D., and Conrad Swartz, M.D.Gordon Parker, M.D., Max Fink, M.D., Edward Shorter, Ph.D., Michael Alan Taylor, M.D., Hagop Akiskal, M.D., German Berrios, M.D., Tom Bolwig, M.D., Walter A. Brown, M.D., Bernard Carroll, M.B.B.S., David Healy, M.D., Donald F. Klein, M.D., Athanasios Koukopoulos, M.D., Robert Michels, M.D., Joel Paris, M.D., Robert T. Rubin, M.D., Robert Spitzer, M.D., and Conrad Swartz, M.D.Published Online:1 Jul 2010https://doi.org/10.1176/appi.ajp.2010.09101525AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Melancholia, a syndrome with a long history and distinctly specific psychopathological features, is inadequately differentiated from major depression by the DSM-IV specifier. It is neglected in clinical assessment (e.g., in STAR*D [1]) and treatment selection (e.g., in the Texas Medication Algorithm Project [2]). Nevertheless, it possesses a distinctive biological homogeneity in clinical experience and laboratory test markers, and it is differentially responsive to specific treatment interventions. It therefore deserves recognition as a separate identifiable mood disorder.Melancholia has been variously described as "endogenous," "endogenomorphic," "autonomous," "type A," "psychotic," and "typical" depression (3–6). In contrast to the current DSM criteria for the melancholia specifier (features of which are often shared with major depression), it has characteristic clinical features (5–7).Clinical Features1. Disturbances in affect disproportionate to stressors, marked by unremitting apprehension and morbid statements, blunted emotional response, nonreactive mood, and pervasive anhedonia—with such features continuing autonomously despite any improved circumstances. The risks for recurrence and for suicide are high.2. Psychomotor disturbance expressed as retardation (i.e., slowed thought, movement, and speech, anergia) or as spontaneous agitation (i.e., motor restlessness and stereotypic movements and speech).3. Cognitive impairment with reduced concentration and working memory.4. Vegetative dysfunction manifested as interrupted sleep, loss of appetite and weight, reduced libido, and diurnal variation—with mood and energy generally worse in the morning.5. Although psychosis is not necessarily a feature, it is often present. Nihilistic convictions of hopelessness, guilt, sin, ruin, or disease are common psychotic themes.Biological ChangesSeveral biological changes occur more frequently in melancholia than in other forms of depressive illness. Three indicative markers are known.1. Hypercortisolemia, reflected in the dexamethasone suppression test (DST). It is common in melancholia and relatively uncommon in nonmelancholic mood disorders (6).2. Psychomotor disturbance measurable by the CORE scale (5), with CORE scores demonstrating a linear relationship with DST nonsuppression rates (8).3. Characteristic disturbances in sleep architecture, with reduced REM latency, increased REM time, and reduced deep sleep (9).TreatmentMelancholic patients respond better to broad-action tricyclic antidepressants than to narrow-action antidepressants (e.g., serotonin uptake inhibitors) (10). They respond well to ECT (11). In comparison to those with nonmelancholic mood disorders, melancholic patients rarely respond to placebos, psychotherapies, or social interventions (12).ConclusionsMelancholia is a lifetime diagnosis, typically with recurrent episodes (5, 6, 13, 14). Within the present classification it is frequently seen in severely ill patients with major depression and with bipolar disorder. Melancholia's features cluster with greater consistency than the broad heterogeneity of the disorders and conditions included in major depression and bipolar disorder. The melancholia diagnosis has superior predictive validity for prognosis and treatment, and it represents a more homogeneous category for research study.We therefore advocate that melancholia be positioned as a distinct, identifiable and specifically treatable affective syndrome in the DSM-5 classification.Address correspondence and reprint requests to Dr. Parker, Black Dog Institute, Prince of Wales Hospital, Hospital Road, Randwick, N.S.W., Australia; g.[email protected]edu.au (e-mail). Editorial accepted for publication January 2010.Dr. Parker is an advisory board member for AstraZeneca, Eli Lilly, and Lundbeck; he has also spoken at and chaired meetings for and received financial sponsorship from AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, Servier, and Wyeth in recent years. Dr. Akiskal has served on speakers or advisory boards for Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Janssen. During 2008–2009 and extending into 2010, Dr. Healy has been, continues to be, and will be an expert witness in legal actions against companies producing sertraline and paroxetine; the cases involve suicide linked to treatment, physical dependence on treatment, and birth defects consequent on treatment with these drugs. Dr. Swartz has equity ownership in Novartis, Somatics, and Sanofi-Aventis and is a director of Somatics. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships. The other authors report no financial relationships with commercial interests.References1 Gaynes BN , Warden D , Trivedi MH , Wisniewski SR , Fava M , Rush AJ : What did STAR*D teach us? results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv 2009; 60:1439–1445 Link, Google Scholar2 Crismon ML , Trivedi M , Pigott TA , Rush AJ , Hirschfeld RM , Kahn DA , DeBattista C , Nelson JC , Nierenberg AA , Sackeim HA , Thase ME : The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999; 60:142–156 Crossref, Medline, Google Scholar3 Kendell RE : The classification of depression: a review of contemporary confusion. Br J Psychiatry 1976; 129:15–28 Crossref, Medline, Google Scholar4 Klein DF : Endogenomorphic depression: a conceptual and terminological revision. Arch Gen Psychiatry 1974; 31:447–454 Crossref, Medline, Google Scholar5 Parker GHadzi-Pavlovic D(eds): Melancholia: A Disorder of Movement and Mood. Cambridge, UK, Cambridge University Press, 1996 Crossref, Google Scholar6 Taylor MA , Fink M : Melancholia: The Diagnosis, Pathophysiology and Treatment of Depressive Illness. 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Recommendations for DSM-5James H. Kocsis, M.D.1 December 2010 | American Journal of Psychiatry, Vol. 167, No. 12Reply to Fleisch et al. LetterGeorge I. Papakostas, M.D.1 December 2010 | American Journal of Psychiatry, Vol. 167, No. 12Reply to Kocsis LetterGordon Parker, M.D., Max Fink, M.D., Edward Shorter, Ph.D., Michael Alan Taylor, M.D., Hagop Akiskal, M.D., German Berrios, M.D., Tom Bolwig, M.D., Walter A. Brown, M.D., Bernard Carroll, M.B.B.S., David Healy, M.D., Donald F. Klein, M.D., Athanasios Koukopoulos, M.D., Robert Michels, M.D., Joel Paris, M.D., Robert T. Rubin, M.D., Robert Spitzer, M.D., and Conrad Swartz, M.D.1 December 2010 | American Journal of Psychiatry, Vol. 167, No. 12Depression and Anxiety, Vol. 27, No. 9Medical Journal of Australia, Vol. 193, No. 9 Volume 167Issue 7 July 2010Pages 745-747 Metrics PDF download History Accepted 1 January 2010 Published online 1 July 2010 Published in print 1 July 2010