Early clinical predictors of long-term morbidity in major depressive disorder.

AIMS: To identify early clinical factors predictive of later morbidity in major depressive disorder (MDD). METHODS: We 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. RESULTS: Three 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. CONCLUSION: Early anxiety symptoms and syndromes and agitated-mixed or psychotic initial depressive episodes predicted more long-term depressive morbidity in MDD.

Child and Adolescent Clinical Features Preceding Adult Suicide Attempts.

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.

Precursors of bipolar disorders: a systematic literature review of prospective studies.

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.

Three-year, naturalistic, mirror-image assessment of adding memantine to the treatment of 30 treatment-resistant patients with bipolar disorder.

BACKGROUND: Developing 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. METHOD: Outpatients 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. RESULTS: The 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. CONCLUSIONS: Memantine 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.

Features preceding diagnosis of bipolar versus major depressive disorders.

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-I (n=109), BD-II (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 7.4 years, and 60.0% vs. 32.8% in adolescence, with far more features in BD than UD 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.

Memantine in the treatment and prophylaxis of bipolar type II mood disorder and co-morbid eating disorder: a case report.

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.

Clinical risk factors for bipolar disorders: a systematic review of prospective studies.

BACKGROUND: Early phases and suspected precursor states of bipolar disorder are not well characterized. We evaluate the prevalence, duration, clinical features and predictive value of non-affective psychopathology as clinical risk factors for bipolar disorder in prospective studies. METHODS: We screened PubMed, CINAHL, PsycINFO, Embase, SCOPUS, and ISI-Web of Science databases from inception up to January 31, 2014, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and searched: bipolar disorder AND [antecedent⁎ OR predict⁎ OR prodrom⁎ OR prospect⁎ OR risk⁎] AND [diagnosis OR development]. We included only English language reports on prospective, longitudinal studies with two structured clinical assessments (intake and follow-up); no DSM intake diagnosis of bipolar-I or -II; diagnostic outcome was bipolar-I or -II. Details of study design, risk factors, and predictive value were tabulated. RESULTS: We found 16 published reports meeting selection criteria, with varying study design. Despite heterogeneity in methods, findings across studies were consistent. Clinical risk factors of bipolar disorder were early-onset panic attacks and disorder, separation anxiety and generalized anxiety disorders, conduct symptoms and disorder, ADHD, impulsivity and criminal behavior. LIMITATIONS: Since risk factors identified in some prospective studies are predictive of other conditions besides bipolar disorder, these preliminary findings require replication, and their sensitivity, specificity and predictive value need to be assessed. CONCLUSIONS: Clinical risk factors for bipolar disorder typically arise years prior to syndromal onset, include anxiety and behavioral disorders with unclear sensitivity and specificity. Prospectively identified clinical risk factors for bipolar disorder are consistent with retrospective and family-risk studies. Combining clinical risk factors with precursors and family-risk may improve early identification and timely and appropriate treatment of bipolar disorder.

Mixed depression: clinical features and predictors of its onset associated with antidepressant use.

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.

Koukopoulos׳ diagnostic criteria for mixed depression: a validation study.

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 validates Koukopoulos׳ criteria as diagnostic for MxD. METHODS: A sample of 435 patients from the International Mood Network (IMN), multi-center, international 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 1.23, 2.84), lower rates of previous bipolar type I diagnosis (OR=0.54, 95% CI -3.28, -0.13), mixed symptoms on the index episode (OR=10.02, 95% CI 2.32, 24.12), rapid cycling course (OR=2.6 95% CI 1.45, 3.56), past substance abuse (OR=3.02, 95% CI 2.01, 5.67) and lower education status (OR=0.44, 95% CI -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 validators and was sensitively and specifically predicted. Contrary to DSM-5, Koukopoulos׳ broad criteria include agitation, irritability and mood lability as core features.

Memantine in the treatment and prophylaxis of bipolar II disorder and comorbid fibromyalgia: a case report.

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.

The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders.

OBJECTIVE: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. METHOD: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. RESULTS: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. CONCLUSIONS: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Mixed features of depression: why DSM-5 is wrong (and so was DSM-IV).

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.

The symptom structure of bipolar acute episodes: in search for the mixing link.

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-naïve patients and the use of rating scales no specific for mixed states.

The sustained mood-stabilizing effect of memantine in the management of treatment resistant bipolar disorders: findings from a 12-month naturalistic trial.

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 cyclers 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.

Suicide in a large population of former psychiatric inpatients.

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.

The origins of electroconvulsive therapy: Prof. Bini's first report on ECT.

In August 1939, at the 3rd International Neurological Congress in Copenhagen, Professor Lucio Bini reported on the first use of electricity to induce a seizure for therapeutic purposes in psychotic patients. At that time, the discovery of ECT amounted to a therapeutic revolution, helping millions of mentally ill patients and furthering the scientific understanding of several disorders. Although electricity had been used to treat several physical ailments and mental disorders, electricity, rather than the convulsive crisis, was considered therapeutic. In modern times von Meduna was the first to clearly recognize the therapeutic value of 'complete' seizures, but it was thanks to Cerletti's dedication to biological research and Bini's contribution that ECT became one of the most effective and safe treatments available. ECT remains a highly effective and safe treatment option and thousands of papers have been published on ECT since the original report by Bini. To celebrate this anniversary, we translated Prof. Bini's original report as an abstract presented in Copenhagen in 1939.